Article

Increased Sensitivity to Thermal Pain and Reduced Subcutaneous Lidocaine Efficacy in Redheads

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Anesthetic requirement in redheads is exaggerated, suggesting that redheads may be especially sensitive to pain. Therefore, the authors tested the hypotheses that women with natural red hair are more sensitive to pain and that redheads are resistant to topical and subcutaneous lidocaine. The authors evaluated pain sensitivity in red-haired (n = 30) or dark-haired (n = 30) women by determining the electrical current perception threshold, pain perception, and maximum pain tolerance with a Neurometer CPT/C (Neurotron, Inc., Baltimore, MD). They evaluated the analogous warm and cold temperature thresholds with the TSA-II Neurosensory Analyzer (Medoc Ltd., Minneapolis, MN). Volunteers were tested with both devices at baseline and with the Neurometer after 1-h exposure to 4% liposomal lidocaine and after subcutaneous injection of 1% lidocaine. Data are presented as medians (interquartile ranges). Current perception, pain perception, and pain tolerance thresholds were similar in the red-haired and dark-haired women at 2,000, 250, and 5 Hz. In contrast, redheads were more sensitive to cold pain perception (22.6 [15.1-26.1] vs. 12.6 [0-20] degrees C; P = 0.004), cold pain tolerance (6.0 [0-9.7] vs. 0.0 [0.0-2.0] degrees C; P = 0.001), and heat pain (46.3 [45.7-47.5] vs. 47.7 [46.6-48.7] degrees C; P = 0.009). Subcutaneous lidocaine was significantly less effective in redheads (e.g., pain tolerance threshold at 2,000-Hz stimulation in redheads was 11.0 [8.5-16.5] vs. > 20.0 (14.5 to > 20) mA in others; P = 0.005). Red hair is the phenotype for mutations of the melanocortin-1 receptor. Results indicate that redheads are more sensitive to thermal pain and are resistant to the analgesic effects of subcutaneous lidocaine. Mutations of the melanocortin-1 receptor, or a consequence thereof, thus modulate pain sensitivity.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... In addition to the description of pain intensities introduced above, the two terminologies relating to both the pain experience and the pain-inducing stimulus are pain threshold and pain tolerance. They are commonly found in pain sensitivity studies or/and the studies involving experimental pain stimulation such as electrical stimulation and thermal stimulation [28,33,48,49]. According to the definitions by IASP, pain threshold is "the minimum intensity of a stimulus that is perceived as painful", and pain tolerance is "the maximum intensity of a pain-producing stimulus that a subject is willing to accept in a given situation." ...
... The temperature reported at pain threshold and pain tolerance are slightly higher than some 51 other studies on average with nearly the same variation. With similar or different stimulation trial design (i.e., temperature rise speed and plateau duration if there is), the average reported pain threshold temperature was 45.7 • C in [56], 44.3 • C in [113], and 42.4 • C among subjects with dark hair in [48]. While the average reported pain tolerance temperature was 47.7 • C among subjects with dark hair in [48] and 45.9 • C in [114] although the average self-report intensity was close to this study (avg.VAS 6.4 [114] v.s. ...
... With similar or different stimulation trial design (i.e., temperature rise speed and plateau duration if there is), the average reported pain threshold temperature was 45.7 • C in [56], 44.3 • C in [113], and 42.4 • C among subjects with dark hair in [48]. While the average reported pain tolerance temperature was 47.7 • C among subjects with dark hair in [48] and 45.9 • C in [114] although the average self-report intensity was close to this study (avg.VAS 6.4 [114] v.s. avg. ...
Thesis
Full-text available
Accurate pain assessment plays an important role in proper pain management, especially among hospitalized people experience acute pain. Pain is subjective in nature which is not only a sensory feeling but could also combine affective factors. Therefore self-report pain scales are the main assessment tools as long as patients are able to self-report. However, it remains a challenge to assess the pain from the patients who cannot self-report. In clinical practice, physiological parameters like heart rate and pain behaviors including facial expressions are observed as empirical references to infer pain objectively. The main aim of this study is to automate such process by leveraging machine learning methods and biosignal processing. To achieve this goal, biopotentials reflecting autonomic nervous system activities including electrocardiogram and galvanic skin response, and facial expressions measured with facial electromyograms were recorded from healthy volunteers undergoing experimental pain stimulus. IoT-enabled biopotential acquisition systems were developed to build the database aiming at providing compact and wearable solutions. Using the database, a biosignal processing flow was developed for continuous pain estimation. Signal features were extracted with customized time window lengths and updated every second. The extracted features were visualized and fed into multiple classifiers trained to estimate the presence of pain and pain intensity separately. Among the tested classifiers, the best pain presence estimating sensitivity achieved was 90% (specificity 84%) and the best pain intensity estimation accuracy achieved was 62.5%. The results show the validity of the proposed processing flow, especially in pain presence estimation at window level. This study adds one more piece of evidence on the feasibility of developing an automatic pain assessment tool from biopotentials, thus providing the confidence to move forward to real pain cases. In addition to the method development, the similarities and differences between automatic pain assessment studies were compared and summarized. It was found that in addition to the diversity of signals, the estimation goals also differed as a result of different study designs which made cross dataset comparison challenging. We also tried to discuss which parts in the classical processing flow would limit or boost the prediction performance and whether optimization can bring a breakthrough from the system’s perspective.
... Three variants (Arg151Cys, Arg160Trp, and Asp294His) are significantly associated with red hair [69], although variance in the gene was necessary but not always sufficient, for red hair production [70]. Although Liem et al. have found increased thermal pain sensitivity [71] in natural red-headed female humans, Mogil et al. have found, in direct opposition, reduced sensitivity to noxious stimuli in female MC1-mutant mice and humans [72]. Delaney et al. appear to also offer some contradictory evidence to Liem et al.'s findings by showing that female mice lacking MC1R showed increased tolerance to noxious heat [73]. ...
... Delaney et al. appear to also offer some contradictory evidence to Liem et al.'s findings by showing that female mice lacking MC1R showed increased tolerance to noxious heat [73]. Females with mutations in the MC1R gene may also have increased anesthetic requirements of desflurane [74], reduced subcutaneous lidocaine efficacy [71], increased analgesia responsiveness for κ-opioids [75], and increased analgesia responsiveness for μ-opioids [72]. ...
... Melanocortin-1 receptor is a G protein-coupled receptor that acts as a key control point of melanogenesis and has been associated with anesthetic efficacy. Liem et al. has found that in red-haired (loss-of-function) female patients, there is increased sensitivity to thermal pain and reduced analgesia with subcutaneous lidocaine [71]. However, Droll et al. found no significant difference in IAN block despite higher dental anxiety [138]. ...
Article
Full-text available
Purpose of review: Pain is multifactorial and complex, often with a genetic component. Pharmacogenomics is a relative new field, which allows for the development of a truly unique and personalized therapeutic approach in the treatment of pain. Recent findings: Until recently, drug mechanisms in humans were determined by testing that drug in a population and calculating response averages. However, some patients will inevitably fall outside of those averages, and it is nearly impossible to predict who those outliers might be. Pharmacogenetics considers a patient's unique genetic information and allows for anticipation of that individual's response to medication. Pharmacogenomic testing is steadily making progress in the management of pain by being able to identify individual differences in the perception of pain and susceptibility and sensitivity to drugs based on genetic markers. This has a huge potential to increase efficacy and reduce the incidence of iatrogenic drug dependence and addiction. The streamlining of relevant polymorphisms of genes encoding receptors, transporters, and drug-metabolizing enzymes influencing the pain phenotype can be an important guide to develop safe new strategies and approaches to personalized pain management. Additionally, some challenges still prevail and preclude adoption of pharmacogenomic testing universally. These include lack of knowledge about pharmacogenomic testing, inadequate standardization of the process of data handling, questionable benefits about the clinical and financial aspects of pharmacogenomic testing-guided therapy, discrepancies in clinical evidence supporting these tests, and doubtful reimbursement of the tests by health insurance agencies.
... MC1R genotype affects the probability of developing malignant melanoma (35), nonmelanoma skin cancer (35)(36)(37), risk for developing complicated sepsis after trauma (38) and development of Parkinson's disease (31,39,40) in humans. Loss-or reducedfunction variants in human MC1R have also been investigated in the response to pain, analgesia and anesthetics (41)(42)(43)(44). Moreover, in Standard Poodle the e 1 /e 1 genotype has been shown to prevent clinical signs of disease in dogs carrying causal variant causing Squamous Cell Carcinoma of the Digit (SCCD) (45). ...
... Genotyping. Genotyping of coat color gene variants of MC1R (2-5), CBD103 (12,13) and ASIP (7-9) loci, and the R301C variant of the MC1R gene was carried out according to manufacturer-recommended standard protocols on a custom-designed Illumina In nium technology bead chip ( (41,42), Illumina, San Diego, Ca, USA). The genotyping quality control measures for this platform were previously described in (41,42). ...
... Genotyping of coat color gene variants of MC1R (2-5), CBD103 (12,13) and ASIP (7-9) loci, and the R301C variant of the MC1R gene was carried out according to manufacturer-recommended standard protocols on a custom-designed Illumina In nium technology bead chip ( (41,42), Illumina, San Diego, Ca, USA). The genotyping quality control measures for this platform were previously described in (41,42). For the purposes of this study, the R301C variant assay ndings were additionally validated with a second genetic technology by Sanger sequencing in representatives of the breed Finnish Lapphund and Cirneco dell'Etna on a ABI3730xl DNA Analyzer platform (Thermo Fisher Scienti c, Waltham, MA, USA) at the Finnish Institute of Molecular Medicine (FIMM) Sequencing Unit as described earlier in (41). ...
Preprint
Full-text available
Background: The Melanocortin 1 Receptor (MC1R) plays a central role in regulation of coat color determination in various species and is commonly referred to as the “E (extension) Locus”. Allelic variation of the MC1R gene is associated with coat color phenotypes EM (melanistic mask), EG (grizzle/domino) and e1-3 (recessive red) in dogs. In addition, a previous study of archeological dog specimens over 10,000 years of age identified a variant p.R301C in the MC1R gene that may have influenced coat color of early dogs. Results: Commercial genotyping of 11,750 dog samples showed the R301C variant of the MC1R gene was present in 35 breeds or breed varieties, at an allele frequency of 1.5% in the tested population. We detected no linkage disequilibrium between R301C and other tested alleles of the E locus. Based on current convention we propose that R301C should be considered a novel allele of the E locus, which we have termed eA for “e ancient red”. Phenotype analysis of owner-provided dog pictures reveals that the eA allele has an impact on coat color and is recessive to wild type E and dominant to the e alleles. In dominant black (KB/*) dogs it can prevent the phenotypic expression of the K locus, and the expressed coat color is solely determined by the A locus. In the absence of dominant black, eA/eA and eA/e genotypes result in the coat color patterns referred to in their respective breed communities as domino in Alaskan Malamute and other Spitz breeds, grizzle in Chihuahua, and pied in Beagle. Conclusions: This study demonstrates a large genotype screening effort to identify the frequency and distribution of the MC1R R301C variant, one of the earliest mutations captured by canine domestication, and citizen science empowered characterization of its impact on coat color.
... The MC1R gene encodes a membrane receptor, which is expressed, in neurons of the periaqueductal gray matter, astrocytes, and Schwann cells activated by melanocortin peptides [16,39]. This receptor may have an important role in the anti-inflammatory brain response [16] and in female specific mediation mechanisms of analgesia [40]. MC1R is also expressed in melanocytes, a cell type with a common embryonic origin with brain cells [41], which determine hair and skin color [42], and certain variants increase the risk for skin cancer (melanoma and non-melanoma skin cancer) [18,19]. ...
... To date, functional evaluation of MC1R variants in other cell types such as the nervous system cells is limited. However, there is evidence that certain variants may also impact physiological conditions beyond skin and hair pigmentation, such as risk of depression disorders [44], pain response [40], and anesthetic requirement [45]. Interestingly, a case-control study indicates that variant p.V92M is associated with the response of desipramine treatment in depression disorder [44]. ...
Article
Despite the recent identification of some novel risk genes for Alzheimer's disease (AD), the genetic etiology of late-onset Alzheimer's disease (LOAD) remains largely unknown. The inclusion of these novel risk genes to the risk attributable to the APOE gene accounts for roughly half of the total genetic variance in LOAD. The evidence indicates that undiscovered genetic factors may contribute to AD susceptibility. In the present study, we sequenced the MC1R gene in 525 Spanish LOAD patients and in 160 controls. We observed that a common MC1R variant p.V92M (rs2228479), not related to pigmentation traits, was present in 72 (14) patients and 15 (9) controls and confers increased risk of developing LOAD (OR: 1.99, 95 CI: 1.08-3.64, p 0.026), especially in those patients whose genetic risk could not be explained by APOE genotype. This association remains and even increased in the subset of 69 patients with typical AD cerebrospinal fluid profile (OR: 3.40 95 CI: 1.40-8.27, p 0.007). We did not find an association between p.V92M and age of onset of AD. Further studies are necessary to elucidate the role of MC1R in brain cells through the different MC1R pathways.
... That being acknowledged, we were intrigued by the results of 2 articles published in the peer-reviewed academic journal Anesthesiology in which clinician scientists sought to verify or refute the anecdotal observations of anesthesiologists, dermatologists, ophthalmologists, and dentists that red-headed patients have a heightened sensitivity to pain with a concomitant increased requirement for volatile (inhalation) and local anesthetic agents. 1,2 Of note, red hair, an autosomal recessive trait, stems from a genetic mutation of the melanocortin-1 receptor gene (MC1R) located on chromosome 16. This gene modifies the responsiveness of the melanocytes' eponymous named receptors to melanocyte-stimulating hormone (secreted by the anterior pituitary gland) altering pigment biosynthesis. ...
... less effective (resistance to the anesthetic) in enhancing their pain tolerance to a noxious electrical current 11.0 mA (8.5, 16.5) than it was among a similarly aged dark-haired cohort of women 20 mA (14.5,>20). 2 In explaining these results the senior author postulated that red-haired subjects have increased anesthetic requirements because MC1R receptors in addition to being located on the surface of melanocytes are also expressed in brain glial cells and neurons of the ventral periaqueductal gray, neural elements known to modulate pain pathways (nociception). 3 Intrigued by the above findings, we searched PubMed and Google Scholar to identify other peerreviewed articles germane to our specialty's scope of practice which described the aberrant medication responses of red-headed patients. We identified another publication also from the anesthesiologists at the University of Louisville who evaluated a mixed gender cohort of 20 red-headed healthy volunteers (mean age 29 AE 6 years) and a similar cohort of non-redhaired participants (mean age 28 AE 7 years) for the sedative effects of an intravenous bolus (2 mg) of the benzodiazepine, midazolam. ...
... ▪ Finally, skin colour, hair colour, freckles and eye colour are related to three mutations in the melanocortin-1 receptor found on chromosome 16 -MC1R (R151C, R160W and D294H), the origin of which have been traced back to 50 to 100 Ka, as a result of hybridization with Neanderthals. Recent research has demonstrated that people with red hair have different sensitivity to pain compared to people with other hair colours, and naturally occurring low vitamin K levels (Mogil, et al., 2005;Liem, et al., 2005;Lalueza-Fox, et al., 2007). In parallel, researchers found that Neanderthal genome affects keratinocytes that protect the skin from environmental damage such as ultraviolet radiation and pathogens. ...
Article
Full-text available
Extended research has shown that the environmental stimuli triggered biomechanical and biochemical alterations in human species since the early Palaeolithic times (Laoupi, 2011; Laoupi, 2016). One unique example is the fact that our remote ancestors chose repeatedly the volcanic environments, where they survived, lived, reproduced and evolved. Other biogenetic alterations helped also Neanderthals to survive in harsh conditions. Even more caves with their ionized internal atmosphere, acoustics, biochemical composition and soothing impact were healing places for humans, places of initiation, education and mystic allegories (Laoupi, 2007).
... This reaction could be produced by an increased susceptibility of these individuals to opioidinduced hyperalgesia. 102 Escitalopram Escitalopram is an SSRI used to treat autism spectrum disorder, but it can also be used to treat neuropathic pain. CYP2C19 is the enzyme responsible for metabolizing escitalopram and individuals can carry up to 30 different alleles. ...
Article
Full-text available
Pharmacogenomics is the study of genetic variants that impact drug effects through changes in a drug's pharmacokinetics and pharmacodynamics. Pharmacogenomics is being integrated into clinical pain management practice because variants in individual genes can be predictive of how a patient may respond to a drug treatment. Pain is subjective and is considered challenging to treat. Furthermore, pain patients do not respond to treatments in the same way, which makes it hard to issue a consistent treatment regimen for all pain conditions. Pharmacogenomics would bring consistency to the subjective nature of pain and could revolutionize the field of pain management by providing personalized medical care tailored to each patient based on their gene variants. Additionally, pharmacogenomics offers a solution to the opioid crisis by identifying potentially opioid-vulnerable patients who could be recommended a nonopioid treatment for their pain condition. The integration of pharmacogenomics into clinical practice creates better and safer healthcare practices for patients. In this article, we provide a comprehensive history of pharmacogenomics and pain management, and focus on up to date information on the pharmacogenomics of pain management, describing genes involved in pain, genes that may reduce or guard against pain and discuss specific pain management drugs and their genetic correlations.
... This phenomenon has been shown in trials compared with non-redheads, where they required significantly more anesthesia (both inhalational and local) for the same clinical effect. 21,22 ...
Article
Full-text available
Background:. The use of local anesthesia has allowed for the excision and repair of lesions of the head and neck to be done in an office-based setting. There is a gap of knowledge on how surgeons can improve operative flow related to the onset of action. A prospective trial was undertaken to determine the length of time for full anesthesia effect in the head and neck regions. Methods:. Consecutive patients undergoing head and neck cutaneous cancer resection over a 3-month period were enrolled in the study. Local anesthesia injection and lesion excision were all done by a single surgeon. All patients received the standard of care of local anesthesia injection. Results:. Overall, 102 patients were included in the prospective trial. The upper face took significantly longer (153.54 seconds) compared with the lower face and ears (69.37 and 60.2 seconds, respectively) (P < 0.001) to become fully anesthetized. In addition, there was no significant difference found when adjusting for the amount of local anesthesia used, type, and size of lesion (P > 0.05). Using the time to full anesthesia effect for each local injection, a heat map was generated to show the relative times of the face and scalp to achieve full effect. Conclusions:. This prospective trial demonstrated that for the same local anesthetic and concentration, upper forehead and scalp lesions take significantly longer to anesthetize than other lesions in the lower face and ear. This can help surgeons tailor all aspects of their practice, which utilizes local anesthesia to help with patient satisfaction and operative flow.
... A TRPV1 point mutation led to lidocaine resistance in mice [140]. There is also evidence that variants in MC1R (encoding melanocortin-1 receptor) reduce lidocaine efficacy [141]. Lidocaine and bupivacaine are metabolized by CYP3A4, and ropivacaine is metabolized by CYP1A2. ...
Article
Full-text available
Pharmacogenetics, the genetic influence on the interpersonal variability in drug response, has enabled tailored pharmacotherapy and emerging 'personalized medicine.' Although oncology spearheaded the clinical implementation of personalized medicine, other specialties are rapidly catching up. In anesthesia, classical examples of genetically mediated idiosyncratic reactions have been long known (e.g., malignant hyperthermia and prolonged apnea after succinylcholine). The last two decades have witnessed an expanding body of pharmacogenetic evidence in anesthesia. This review highlights some of the prominent pharmacogenetic associations studied in anesthesia and pain management, with special focus on pediatric anesthesia.
... Moreover, women with provoked vestibulodynia are 2.5 times as likely to exhibit loss-of-function melanocortin-1 receptor polymorphisms that may interfere with the downregulation of proinflammatory cytokines and adhesion molecules generated by the nuclear factor-B pathway (90,91). This polymorphism may impact a broad range of pain mechanisms because the melanocortin-1 receptor mediates -opioid analgesia in women, modulates -opioid analgesia, and pain thresholds in women (92)(93)(94)(95). Indeed, most of the genetic polymorphisms identified in genito-pelvic pain populations appear to impact inflammatory cascades, host-pathogen interactions, and pain sensitivity (88). ...
Chapter
Efficient clinical assessment, diagnosis, and treatment of women with sexual pain requires a comprehensive knowledge of the physiological systems underlying acute and chronic nociception. Whereas acute episodes of sexual pain are mediated by end‐organ pathology, persistent sexual pain must be conceptualized in terms of ongoing peripheral, spinal, and brain mechanisms that can lead to dramatic functional changes in nociception and enhanced pain perception. This state‐of‐the‐art review draws from rigorous rodent and human research to explore potential mechanisms underlying the symptom configurations associated with sexual pain. A strong understanding of these mechanisms is essential for the assessment and strategic treatment of women who present with unremitting sexual pain.
... MC1R genotype affects the probability of developing malignant melanoma (24), nonmelanoma skin cancer (24)(25)(26), risk for developing complicated sepsis after trauma (27) and development of Parkinson's disease (20,28,29) in humans. Loss-or reducedfunction variants in human MC1R have also been investigated in the response to pain, analgesia and anesthetics (30)(31)(32)(33) Photos representing the phenotypic impact of the eA allele. In the presence of KB at the K locus, eA/e1 genotype produces a partial recessive red phenotype representing the dogs A locus genotype (fawn) A) which can be seemingly indistinguishable from recessive red typical in the breed Cirneco dell'Etna B) differing from the rare KB solid eumelanin shade in Cirneco dell'Etna (in which the eumelanin shade is brown due to mutation in the TYRP1 gene). ...
Preprint
Full-text available
Background The Melanocortin 1 Receptor (MC1R) plays a central role in regulation of coat color determination in dogs and is commonly referred to as the “E (extension) Locus”. Allelic variation of the MC1R gene is associated with coat color phenotypes EM (melanistic mask), EG (grizzle/domino) and e1–3 (recessive red) in dogs. In addition, a previous study of archeological dog specimens over 10,000 years of age identified a variant p.R301C in the MC1R gene that may have influenced coat color of early dogs. Results Commercial genotyping of 11,726 dog samples showed the R301C variant of the MC1R gene was present in 34 breeds or breed varieties, at an allele frequency of 1.48% in the tested population. We detected no linkage disequilibrium between R301C and other tested alleles of the E locus. Based on current convention we propose that R301C should be considered a novel allele of the E locus, which we have termed eA for “e ancient”. Phenotype analysis of owner-provided dog pictures reveals eA allele has an impact on coat color and is recessive to wild type E and dominant to the e alleles. In dominant black (KB/*) dogs it can prevent the expression of the K locus, and the expressed coat color is solely determined by the A locus. In the absence of dominant black, eA/eA and eA/e genotypes result in the coat color patterns referred to in their respective breed communities as domino in Alaskan Malamute and other Spitz breeds, grizzle in Chihuahua, and pied in Beagle. Conclusions This study demonstrates a large genotype screening effort to identify the frequency and distribution of the MC1R R301C variant, one of the earliest mutations captured by canine domestication, and citizen science empowered characterization of its impact on coat color.
... Genetic variability has also been associated to risk of local anesthetics toxicity. MC1R variants with decreased lidocaine efficacy has also been described [76]. ...
Article
Full-text available
Purpose of review: The current review will discuss the current literature on genetics of pain and analgesia, with special emphasis on perioperative setting. We will also discuss pharmacogenetics-based management guidelines, current clinical status and future perspectives. Recent findings: Recent literature suggests that the interindividual variability in pain and postoperative analgesic response is at least in part because of one's genetic make-up. Some of the well characterized polymorphisms that are associated with surgical pain and opioid-related postoperative adverse outcomes are described in catechol-O-methyl transferase, CYP2D6 and μ-opioid receptor (OPRM1), ATP-binding cassette subfamily B member 1, ABCC3, organic cation transporter 1 genes. Clinical Pharmacogenetics Implementation Consortium has put forth recommendations on CYP2D6 genotype-based opioid selection and dosing. The list of drug-gene pairs studied continue to expand. Summary: Pharmacogenetic approach marks the dawn of personalized pain medicine both in perioperative and chronic pain settings.
... Moreover, women with provoked vestibulodynia are 2.5 times as likely to exhibit loss-offunction melanocortin-1 receptor polymorphisms that may interfere with the downregulation of proinflammatory cytokines and adhesion molecules generated by the NF-κB pathway [90,91]. This polymorphism may impact a broad range of pain mechanisms because the melanocortin-1 receptor mediates κ-opioid analgesia in women and modulates μ-opioid analgesia and pain thresholds in women [92][93][94][95]. Indeed, most of the genetic polymorphisms identified in genito-pelvic pain populations appear to impact inflammatory cascades, host-pathogen interactions, and pain sensitivity [88]. ...
Chapter
Full-text available
Nociception includes the detection, transmission, and modulation of noxious sensory information through the peripheral and central nervous system. It begins at the surface of the skin, where a subset of sensory neurons called nociceptors encode stimuli in the environment that can threaten the integrity of the body. Estrogen is implicated in sensation and nociception at peripheral, spinal, and supraspinal levels. In the brain, estrogen promotes endogenous opioid analgesia and spinal inhibition of pain. Referred pain is among the least appreciated mechanisms underlying genito‐pelvic pain and other comorbid pain syndromes. Inflammation, the most common cause of peripheral sensitization, may account for a limited degree of pain pathophysiology observed in women with genito‐pelvic pain. Central sensitization provides a physiological mechanism for sustained pain in the absence of the precipitating stimulus. When central sensitization and referred pain co‐occur, secondary hyperalgesia may take a different form: silent nociceptors can mediate new regions of cutaneous or deep muscle hypersensitivity.
... Point mutations in MC1R are often cited as responsible for the red-haired phenotype [69]. Individuals with this phenotype have been shown to exhibit greater anesthetic requirement [70] and increased sensitivity to thermal pain [71]. It has also been determined that females with two variant MC1R alleles experience enhanced analgesia with pentazocine, a kappa-opioid receptor agonist [72]. ...
Article
Full-text available
Chronic neuropathic pain (CNP) is one of the most significant unmet clinical needs in modern medicine. Alongside the lack of effective treatments, there is a great deficit in the availability of objective diagnostic methods to reliably facilitate an accurate diagnosis. We therefore aimed to determine the feasibility of a simple diagnostic test by analysing differentially expressed genes in the blood of patients diagnosed with CNP of the lower back and compared to healthy human controls. Refinement of microarray expression data was performed using correlation analysis with 3900 human 2-colour microarray experiments. Selected genes were analysed in the dorsal horn of Sprague–Dawley rats after L5 spinal nerve ligation (SNL), using qRT-PCR and ddPCR, to determine possible associations with pathophysiological mechanisms underpinning CNP and whether they represent translational biomarkers of CNP. We found that of the 15 potential biomarkers identified, tissue inhibitor of matrix metalloproteinase-1 (TIMP1) gene expression was upregulated in chronic neuropathic lower back pain (CNBP) (p = 0.0049) which positively correlated (R = 0.68, p = ≤0.05) with increased plasma TIMP1 levels in this group (p = 0.0433). Moreover, plasma TIMP1 was also significantly upregulated in CNBP than chronic inflammatory lower back pain (p = 0.0272). In the SNL model, upregulation of the Timp1 gene was also observed (p = 0.0058) alongside a strong trend for the upregulation of melanocortin 1 receptor (p = 0.0847). Our data therefore highlights several genes that warrant further investigation, and of these, TIMP1 shows the greatest potential as an accessible and translational CNP biomarker. Electronic supplementary material The online version of this article (doi:10.1007/s12035-017-0492-8) contains supplementary material, which is available to authorized users.
... MC1R genotype affects the probability of developing malignant melanoma [35], nonmelanoma skin cancer [35][36][37], risk for developing complicated sepsis after trauma [38] and development of Parkinson's disease [31,39,40] in humans. Lossor reduced-function variants in human MC1R have also been investigated in the response to pain, analgesia and anesthetics [41][42][43][44]. Moreover, in Standard Poodle the e 1 / e 1reduced-function variants in human genotype has been shown to prevent clinical signs of disease in dogs carrying causal variant causing Squamous Cell Carcinoma of the Digit (SCCD) [45]. ...
Article
Full-text available
Background The Melanocortin 1 Receptor (MC1R) plays a central role in regulation of coat color determination in various species and is commonly referred to as the “E (extension) Locus”. Allelic variation of the MC1R gene is associated with coat color phenotypes EM (melanistic mask), EG (grizzle/domino) and e1–3 (recessive red) in dogs. In addition, a previous study of archeological dog specimens over 10,000 years of age identified a variant p.R301C in the MC1R gene that may have influenced coat color of early dogs. Results Commercial genotyping of 11,750 dog samples showed the R301C variant of the MC1R gene was present in 35 breeds or breed varieties, at an allele frequency of 1.5% in the tested population. We detected no linkage disequilibrium between R301C and other tested alleles of the E locus. Based on current convention we propose that R301C should be considered a novel allele of the E locus, which we have termed eA for “e ancient red”. Phenotype analysis of owner-provided dog pictures reveals that the eA allele has an impact on coat color and is recessive to wild type E and dominant to the e alleles. In dominant black (KB/*) dogs it can prevent the phenotypic expression of the K locus, and the expressed coat color is solely determined by the A locus. In the absence of dominant black, eA/eA and eA/e genotypes result in the coat color patterns referred to in their respective breed communities as domino in Alaskan Malamute and other Spitz breeds, grizzle in Chihuahua, and pied in Beagle. Conclusions This study demonstrates a large genotype screening effort to identify the frequency and distribution of the MC1R R301C variant, one of the earliest mutations captured by canine domestication, and citizen science empowered characterization of its impact on coat color.
... Each outcome was measured three times and the mean calculated before moving on to the next outcome. The method of descending limits was used for cold stimuli and the method of ascending limits was used for heat stimuli with baseline temperature set at 32°C, and the rate of temperature change was 1°C/s (Liem et al., 2005). Participants pressed a handheld button to stop delivery of the stimulus and signify detection of the sensation under investigation. ...
Article
Background: The aim of this study was to investigate the influence of body fat percentage and its distribution on sensory detection and pain sensitivity responses to experimentally induced noxious stimuli in otherwise pain-free individuals. Methods: Seventy-two participants were divided into three equal groups according to their body mass index (BMI: normal, overweight and obese). Percentage body fat was estimated using a four-site skinfold method. Measurements of cold pressor pain threshold, tolerance and intensity; contact thermal sensory detection and heat pain threshold and tolerance (TSA-II - NeuroSensory Analyzer, Medoc); and blunt pressure pain threshold (algometer, Somedic SenseLab AB) were taken at the waist and thenar eminence. Results: Mean ± SD pressure pain threshold of the obese group (620.72 ± 423.81 kPa) was significantly lower than normal (1154.70 ± 847.18 kPa) and overweight (1285.14 ± 998.89 kPa) groups. Repeated measures ANOVA found significant effects for site for cold detection threshold (F1,68 = 8.3, p = 0.005) and warm detection threshold (F1,68 = 38.69, p = 0.001) with waist having lower sensory detection thresholds than thenar eminence. For heat pain threshold, there were significant effects for site (F1,68 = 4.868, p = 0.031) which was lower for waist compared with thenar eminence (mean difference = 0.89 °C). Conclusion: Obese individuals were more sensitive than non-obese individuals to pressure pain but not to thermal pain. Body sites may vary in their response to different types and intensities of stimuli. The inconsistency of findings within and between research studies should catalyse further research in this field. Significance: This study provided evidence that body mass index and distribution of body fat can influence sensory detection and pain sensitivity. Obese individuals were more sensitive than normal range body mass index individuals to pressure pain but not to thermal pain. Pain response varied according to subcutaneous body fat at different body sites. These findings strengthen arguments that weight loss should be a significant aspect of a pain management programme for obese pain patients.
... Humans and mice with red hair exhibit altered pain thresholds, increased nonopioid analgesic requirements, and enhanced responses to opioid analgesics (1)(2)(3)(4)(5)(6). Red hair in both species is caused by lossof-function variant alleles of the melanocortin 1 receptor (MC1R), a G s -coupled receptor expressed on melanocytes, the pigmentproducing cells of the skin (7). ...
Article
Full-text available
Humans and mice with natural red hair have elevated basal pain thresholds and an increased sensitivity to opioid analgesics. We investigated the mechanisms responsible for higher nociceptive thresholds in red-haired mice resulting from a loss of melanocortin 1 receptor (MC1R) function and found that the increased thresholds are melanocyte dependent but melanin independent. MC1R loss of function decreases melanocytic proopiomelanocortin transcription and systemic melanocyte-stimulating hormone (MSH) levels in the plasma of red-haired ( Mc1r e/e ) mice. Decreased peripheral α-MSH derepresses the central opioid tone mediated by the opioid receptor OPRM1, resulting in increased nociceptive thresholds. We identified MC4R as the MSH-responsive receptor that opposes OPRM1 signaling and the periaqueductal gray area in the brainstem as a central area of opioid/melanocortin antagonism. This work highlights the physiologic role of melanocytic MC1R and circulating melanocortins in the regulation of nociception and provides a mechanistic framework for altered opioid signaling and pain sensitivity in red-haired individuals.
... However, in humans, subjects' genetic characteristics must be measured rather than assumed. For example, resistance to subcutaneous lidocaine was measured in women with red hair that were assumed to have the mutated MCR1 gene even though genetic mutations in MCR1 were not directly measured (Liem et al., 2005). The same group has also shown that genetic mutations in MCR1 are associated with an increased requirement for general anesthesia in redheads (Liem et al., 2004). ...
Article
Full-text available
A gap exists between translating basic science research into effective pain therapies in humans. While preclinical pain research has primarily used animal models to understand biological processes, a lesser focus has been toward using animal models to fully consider other components of the pain experience, such as psychological and social influences. Herein, we provide an overview of translational studies within pain research by breaking them down into purely biological, psychological and social influences using a framework derived from the biopsychosocial model. We draw from a wide landscape of studies to illustrate that the pain experience is highly intricate, and every attempt must be made to address its multiple components and interactors to aid in fully understanding its complexity. We highlight our work where we have developed animal models to assess the cognitive and social effects on pain modulation while conducting parallel experiments in people that provide proof-of-importance for human pain modulation. In some instances, human pain research has sparked the development of novel animal models, with these animal models used to better understand the complexity of phenomena considered to be uniquely human such as placebo responses and empathy.
... A genetic association study 13 as well as experiments performed with animal models of the redhead phenotype 14 showed that the MC1R plays a crucial role in the association between red hair and Parkinson's disease. Anecdotal observations as well as several case-controls studies suggested a higher pain sensitivity 15 , an increased risk of endometriosis 16,17 , and an increased bleeding tendency 18,19 of red haired women. It must be mentioned, however, that the observed effect sizes are usually small and that some studies provided negative results. ...
Article
Full-text available
About 1–2% of people of European origin have red hair. Especially female redheads are known to suffer higher pain sensitivity and higher incidence of some disorders, including skin cancer, Parkinson’s disease and endometriosis. Recently, an explorative study performed on 7,000 subjects showed that both male and female redheads score worse on many health-related variables and express a higher incidence of cancer. Here, we ran the preregistered study on a population of 4,117 subjects who took part in an anonymous electronic survey. We confirmed that the intensity of hair redness negatively correlated with physical health, mental health, fecundity and sexual desire, and positively with the number of kinds of drugs prescribed by a doctor currently taken, and with reported symptoms of impaired mental health. It also positively correlated with certain neuropsychiatric disorders, most strongly with learning disabilities disorder and phobic disorder in men and general anxiety disorder in women. However, most of these associations disappeared when the darkness of skin was included in the models, suggesting that skin fairness, not hair redness, is responsible for the associations. We discussed two possible explanations for the observed pattern, the first based on vitamin D deficiency due to the avoidance of sunbathing by subjects with sensitive skin, including some redheads, and second based on folic acid depletion in fair skinned subjects, again including some (a different subpopulation of) redheads. It must be emphasized, however, that both of these explanations are only hypothetical as no data on the concentration of vitamin D or folic acid are available for our subjects. Our results, as well as the conclusions of current reviews, suggest that the new empirical studies on the concentration of vitamin D and folic acids in relation to skin and hair pigmentation are urgently needed.
Chapter
Pain triggers the “stress response” with associated physiological changes, and often results in prolonged hospital stay and increases the potential for secondary problems, such as hospital‐associated infections, immune suppression and secondary illness, inappetence and cachexia. Chronic pain is experienced by millions of dogs and cats, and many of these present with an acute problem or require surgical intervention for various ill or injury conditions. The insidious onset of signs, their similarity to those associated with the infirmities of age, makes owner recognition of their pet's pain more difficult. This chapter highlights key points in assessment of pain in animals. In considering these points, the veterinarian and veterinary technician/nurse (VT/N) will rapidlygain experience and confidence in assessing and treating pain in animals. The levels of pain were determined by the analgesic, the dose and the duration of action of the analgesic required to effectively control the animal's pain.
Article
Introduction: Recent studies have investigated the relationship between pain perception and specific phenotypes such as red hair color and various eye colors. Further investigations into biomarkers as they relate to pain could be useful in understanding underlying genetic components involved in these pathways. Additionally, it would be clinically useful to determine if a patient would be more likely to experience pain during dental treatment based on eye color. The purpose of this study was to investigate a link between eye color and perceived injection pain in healthy, asymptomatic white women. Methods: Three hundred healthy, adult, white female patients were included, 133 with dark eyes and 167 with light eyes. Dental anxiety was assessed with the Corah Dental Anxiety Scale. Subjects with their eye color masked by dark glasses received a right maxillary lateral incisor infiltration of 1 cartridge of 2% lidocaine with 1:100,000 epinephrine. Patients rated their injection pain on a 170-mm Heft-Parker visual analog scale. Photographs of the subjects' eyes were taken after the infiltrations and categorized into dark- and light-eyed groups by 3 independent observers. Comparisons for injection pain were analyzed using analysis of variance and the Tukey-Kramer test. Results: No significant differences were found for pain of injection between dark- or light-eyed subjects. Conclusions: Eye color was not shown to be a predictor for injection pain in white women. Therefore, eye color would not be clinically useful in determining if a patient would be more likely to experience pain during dental treatment.
Chapter
Pain is present in many medical, all traumatic and inflammatory conditions and, without appropriate analgesic management, all post-operative veterinary patients. Pain associated with the abdominal viscera may produce a low to normal heart rate due to vagal activity. Maladaptive pain is generated from a malfunction of neurologic transmission due to the ongoing "acute" pain and serves no physiological purpose. The humane factor must be considered with administration of analgesics and modalities to prevent and treat pain prior to the patient experiencing the noxious sensation. Pain assessment measures have been utilized by veterinary researchers as a way to quantify pain in various studies and to analyse data. These consist of verbal rating scales (VRS), simple descriptive scales (SDS), numerical rating scales (NRS) and the visual analogue scale (VAS). Glasgow Composite Measure Pain Scale and its short form (CMPS-SF) is a clinical decision-making tool when used in conjunction with clinical judgement.
Article
Individual variation in opioid sensitivity can have a profound impact on the safety and efficacy of equine veterinary treatments, with the ability to adequately manage equine pain in a clinical setting currently limited. This review aims to explore the overlap between biological mechanisms associated with opioid metabolism and those mechanisms associated with coat colour in horses as has been documented in humans, with particular focus on the melanocortin‐1 receptor (MC1R) gene. In the future, the use of the MC1R coat colour genotype could help to indicate variable opioid sensitivities thereby greatly improving the use of opioids in clinical settings. The MC1R gene has a well‐established role in melanogenesis and pigment switching, but involvement in the pain‐modulating periaqueductal grey (PAG) descending pathway and in immune responses, both of which contain opioid receptors, has also been suggested in humans. However, this relationship between opioid metabolism and the connection to the three known MC1R variants (EE, Ee and Eea) in horses is yet to be explored.
Article
Full-text available
Red hair is associated in women with pain sensitivity. This medical condition, and perhaps others, seems facilitated by the combination of being red-haired and female. We tested this hypothesis by questioning a large sample of Czech and Slovak respondents about the natural redness and darkness of their hair, their natural eye color, their physical and mental health (24 categories), and other personal attributes (height, weight, number of children, lifelong number of sexual partners, frequency of smoking). Red-haired women did worse than other women in ten health categories and better in only three, being particularly prone to colorectal, cervical, uterine, and ovarian cancer. Red-haired men showed a balanced pattern, doing better than other men in three health categories and worse in three. Number of children was the only category where both male and female redheads did better than other respondents. We also confirmed earlier findings that red hair is naturally more frequent in women than in men. Of the ‘new’ hair and eye colors, red hair diverges the most from the ancestral state of black hair and brown eyes, being the most sexually dimorphic variant not only in population frequency but also in health status. This divergent health status may have one or more causes: direct effects of red hair pigments (pheomelanins) or their by-products; effects of other genes that show linkage with genes involved in pheomelanin production; excessive prenatal exposure to estrogen (which facilitates expression of red hair during fetal development and which, at high levels, may cause health problems later in life); evolutionary recentness of red hair and corresponding lack of time to correct negative side effects; or genetic incompatibilities associated with the allele Val92Met, which seems to be of Neanderthal origin and is one of the alleles that can cause red hair.
Chapter
Safe, ethical, and effective prescription of opioids is predicated upon a thorough understanding of the biologic systems wherein/upon which they act.
Article
This study investigates the moderator relationship between three psychological variables on pain threshold and tolerance: pain anticipation, neuroticism and extraversion. It is hypothesised that (a) a significant effect of anticipation on both pain threshold and tolerance will exist; wherein high-intensity pain anticipation will predispose lower pain threshold and tolerance, and (b) high neuroticism and low extraversion will moderate this relationship. The study was conducted using 76 participants who completed the cold pressor test under one of three conditions: control condition, intense-pain expectant condition or low-pain expectant. The results of the study showed no significant effect of anticipation and no significant moderator relationship for neuroticism or extraversion on pain threshold and tolerance, thus both hypotheses are not supported. Implications for future research are discussed providing new and unique findings, as no prior research into the moderator relationship between anticipation, personality traits and pain currently exists.
Conference Paper
Full-text available
Background The ineffective management of the perioperative pain can affect the length of hospital stay by increasing the risk of postoperative complications (1). There are multiple analgesia techniques; today, opioids remain the most widely used drugs for pain control even if side effects can overbalance the analgesic advantage and affect the general state of the patient. Dexmedetomidine is a selective alpha2 agonist, with a specificity eight times that of clonidine (2). Dexmedetomidine provides sedative, anxiolytic, sympatholytic and analgesic effects, and minimal depression of respiratory function, thus it has been widely used in intensive care units (ICUs) and for anesthesia for several years (3). This review will evaluate the dexmedetomidine analgesic and opioid-sparing effect. Furthermore, we will evaluate the effectiveness and safety of dexmedetomidine in the perioperative pain management. We will prepare this systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P 2015 Guidelines) (4). The review protocol was registered on the PROSPERO International Prospective Register of Systematic Reviews (Registration Number CRD42018086687, 30/01/2018). Material and Methods The population will be patients undergoing general anesthesia. The intervention will be the perioperative infusion of dexmedetomidine. The comparator will be patients undergoing General anesthesia conducted without perioperative infusion of Dexmedetomidine. The primary outcomes will be I) postoperative pain evaluation and/or II) opioid-sparing effect. Secondary outcome will be a) respiratory depression requiring ventilation and/or ICU admission b) hypotension requiring fluid infusion and/or amine administration c) bradycardia requiring vasoactive drugs d) needing of prolonged length of hospital stay. We will include both RCT and observational studies (including cohort and case–control studies) that have use dexmedetomidine infusion in general anaesthesia. Quantitative papers will, where possible be pooled in statistical meta-analysis: Risk differences (RDs) will be used as the meta-analytic measure of association We will perform a bibliographic search using several databases: MEDLINE, EMBASE, CENTRAL (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials and the JBISRIR (JBI Database of Systematic Review and Implementation Report). The search query will be: (general anesthesia OR general an*) AND dexmedetomidine AND (analgesics, opioid OR analgesi* OR opioid*). The reference list of all identified reports and articles will be searched for additional studies. The search strategy aims to find only studies published in English language and in peer-reviewed journals in full with no restriction on publication date. Two authors (AA and AB) will independently evaluate the titles and abstracts of potentially eligible studies. Data will be extracted independently according to the MOOSE guideline and the results were cross-checked. Any disagreements on study eligibility or data extraction were resolved according to a third reviewer’s opinion (MF). Study quality will be independently assessed by two authors (AA and AB): STROBE guidelines will be used to evaluate observational studies, CONSORT guidelines will be used to evaluate RCT. Discussion The review's goal is to evaluate the effectiveness of peri-operative infusion of dexmedetomidine for post-operative pain control in order to reduce opioid consumption and concerning adverse effects in patients undergoing general anesthesia. Furthermore, we will evaluate the safety of dexmedetomidine in the perioperative pain management. Bibliography (1) Luise Jessen Lundorf, Helene Korvenius Nedergaard, Ann Merete Møller Perioperative dexmedetomidine for acute pain after abdominal surgery in adults. Cochrane Anaesthesia, Critical and Emergency Care Group (2) Virtanen R, Savola JM, Saano V, Nyman L. Characterization of the selectivity, specificity and potency of medetomidine as an alpha 2-adrenoceptor agonist. Eur J Pharmacol. 1988;150:9–14. (3) Belleville JP, Ward DS, Bloor BC, Maze M. Effects of intravenous dexmedetomidine in humans. I. Sedation, ventilation, and metabolic rate. Anesthesiology. 1992;77:1125–33. (4) Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA. Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4(1):1. doi: 10.1186/2046-4053-4-1 (5) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB. JAMA. 2000 Apr 19;283(15):2008-12.
Chapter
The pharmacokinetics (PK), pharmacodynamics (PD) and side effect profile of most medications used in children differ from those in adults; these differences are most pronounced in neonates. PK are affected by maturation of organ function and body composition, altered protein binding, distinct disease spectrum, diverse behaviour and dissimilar receptor patterns (Kearns et al., N Engl J Med 349(12):1157–67, 2003). The capacity of the end organ, such as the brain, heart or skeletal muscle, to respond to medications may also differ in children compared with adults (PD effects). Dose modification to achieve the desired clinical response and avoid toxicity is required for children. Dose calculations are based on knowledge of PK and PD (Anderson and Holford, Arch Dis Child. 98(9):737–44, 2013).
Chapter
The dermatologic indications for local and regional infiltrated anesthesia are abundant. Local infiltrative anesthesia is considered safe and effective for an array of procedures including excisions, biopsies, wound closures, skin grafting, cauterization, nonablative laser, and ablative skin resurfacing. Few contraindications to local and regional infiltrated anesthesia exist but should be screened for during the preoperative consultation. Numerous techniques for achieving adequate local and regional anesthesia have been described, including practices to lessen the pain associated with injection. Common side effects of local infiltrative anesthesia include pain, erythema, edema, bleeding, and ecchymoses. While overall well tolerated and commonly used, local and regional infiltrative anesthetic procedures do carry risks for toxicity and death. A comprehensive understanding of the pathophysiology, technique, and potential adverse events of various local and regional infiltrated anesthetics is critical to improve patient satisfaction and safety.
Conference Paper
Full-text available
Background Several surgical procedures are performed every day around the world, most of them are discomfortable for patients. Some diagnostic procedures or short surgical interventions may be performed with local anesthesia. A ‘short’ procedure may be described as an intervention anticipated to take less than 60 minutes. Local anesthesia offers an indisputable advantage regarding the pain control with minimal systemic side-effects and good patient tolerability. Tramadol is an atypical synthetic opioid analgesic. It is considered a weak opioid due to its relatively low affinity for μ-opioid receptor [1]. Tramadol and its active metabolite bind to μ-opioid receptors in the central nervous system resulting in inhibition of ascending pain pathways and also inhibits the reuptake of norepinephrine and serotonin, involved in the descending inhibitory pain pathway, associated with pain relief [2]. In addition, tramadol has been proved to exert a local anesthetic effect on peripheral nerves in both clinical and laboratory studies. The mechanism of action of tramadol is similar to that of hydrophobic local anesthetics [3]. Methods A systematic review of the literature will be conducted following the PRISMA guidelines [4]. Either randomized controlled trials and observational studies, in which Tramadol is locally administrated, will be included. The search will be made using several electronic database: PubMed, EMBASE, CENTRAL and The JBI Database of Systematic Review and Implementation Report (JBISRIR). The intervention will be the local administration of Tramadol alone or as adjuvant to other anesthetics used for pain control. The comparison will be: 1. Placebo 2. No treatment 3. Standard local anesthetic-based therapy according to current guidelines. The primary outcome will be the pain control as: i) pain intensity reduction of at least 2, 3 or 4 points or by achieving a VAS score < 3 and/or ii) pain intensity reduction of at least 2, 3 or 4 points or by achieving a NRS score < 3[5] The secondary outcomes will be the: A. drugs consumption as A1. reduction of tramadol rescue dose and/or A2. reduction of others analgesic drugs consumption B. alterated vital signs as B1. tachycardia (heart rate > physiological range by age) and/or B2. hypertension (blood pressure > physiological range by age) and/or B3. desaturation (SpO2 < physiological range by age) Inclusion criteria of the enrolled studies will be: i) clear description of local tramadol administration ii) publication in peer-reviewed journals iii) English language iv) published in full Exclusion criteria: i) studies describing the tramadol uses for no surgical procedures ii) letter/comment, case report/series, systematic/narrative reviews, abstract, book chapter iii) pre-procedural or peri-procedural intravenous use of tramadol iv) intrathecal or troncular injection of tramadol. Discussion The aim of this systematic review is to investigate the effectiveness of local administration of tramadol for post-procedural pain control in order to reduce side-effects related to the systemic administration of analgesic drugs and reduce patient’s discomfort. This systematic review will be conducted in accordance with the Centre of Reviews and Dissemination (CRD) guidance for undertaking reviews in health care and registered on the PROSPERO Registry of systematic reviews: CRD4201808738.
Chapter
Pharmacogenomics is the study of how genetic differences between individuals affect pharmacokinetics and pharmacodynamics. These differences are apparent to clinicians when taking into account the wide range of responses to medications given in clinical practice. The implementation of preoperative pharmacogenomics will allow us to better care for our patients by delivering personalized, safer medicine. This chapter describes the current state of pharmacogenomics as it relates to perioperative care and how clinicians can use these tools to improve patient outcomes.
Article
Osteoarthritis of the knee is one of the leading causes of disability and work limitations in the United States, resulting in significantly decreased work productivity and loss of work. The definitive treatment of choice for end-stage osteoarthritis is total knee arthroplasty. However, up to 34% of patients who undergo TKA experience chronic pain. Long-term pain continues to pose a significant burden and directly undermines the goal in treatment of patients with osteoarthritis, and persistent postoperative pain is a major concern to the orthopaedic community. Finding ways to reduce the number of patients experiencing persistent postoperative pain, as well as reducing the severity of the pain felt, is absolutely necessary. There is a growing cohort of evidence that suggests that the experience of pain is felt differently among patients, and there are many factors that may play a role in this experience. The difference in experience may have a genetic basis and, in the context of the growing opioid crisis in the United States, these genetic differences may explain variations in opioid effectiveness as well. This review examines the current literature that identifies specific factors responsible for the development of pain, including ethnicity, race, psychosocial, and, most notably, genetic factors.
Article
Full-text available
The knowledge about horse coat color genetics has several applications, ranging from selection of desirable characteristics, understanding of the domestication process and as an auxiliary diagnosis in the clinic. It is essential for the veterinary professional to have a basic understanding of the genetic and functional mechanisms of the coatings, to better provide patient care and help breeders/owners of horses. However, currently the literature on coat genetics in Portuguese is out-of-date, and many unfounded prejudices continue to be disseminated due to the lack of scientific knowledge. This article covers the major topics on horse coat color genetics, addressing phenotypic characteristics, detrimental pleiotropies and physiological mechanisms related to the coat of domestic horses.
Article
Behavior is a valuable quantitative trait in the horse because of its impact on performance, work, recreation, and prerequisite close interactions with humans. This article reviews what is known about the genetics of behavior in horses with an emphasis on the genetic basis for temperament traits, neuroendocrine function, and stereotypic behavior. The importance of using modern molecular genetic techniques to the study of equine behavior and recommendations for future research are also discussed. Ultimately, these studies enhance the understanding of the biology of behavior in the horse, improve handler and rider safety, and benefit horse welfare.
Conference Paper
Full-text available
Background and Objective This study evaluates the efficacy and safety of a sufentanil sublingual tablet system (SSTS) for the management of postoperative pain following open abdominal surgery (1). Based on the results of three phase III studies, the SSTS has been approved in the EU for the management of acute moderate to severe postoperative pain in adults in a hospital setting. Methods Patients undergoing major abdominal surgery were included from the General Surgical Unit of the Regina Apostolorum Hospital. Patients following surgery with pain intensity of greater than 4 and smaller than 8 on an 11-point numerical rating scale were randomized to receive SSTS dispensing a 15-μg sufentanil tablet sublingually with a 20-minute lockout. Elegible patients met the following criteria: adults older than 18 yr scheduled for major abdominal surgery, ASA 1-3, general anaesthesia or spinal anahestesia (without using intratecal opioids); Exclusion criteria included : ASA ˃ 3, patients with OSAS, or unable to understand the use of SSTS, patients with story of alcoholism or drug dependence. Patients were observed at regular intervals during a 72-hour evaluation period. Numeric Rating Scale ( NRS ) scores were used to assess analgesia and satisfaction with therapy. The primary end point was time-weighted summed pain intensity difference (SPID) over 48 hours. Secondary end points included SPID and total pain relief (TOTPAR) for up to 72 hours and patient and health care provider global assessments of the method of pain control. Results The SSTS was associated with a more rapid onset of analgesia and higher rates of success, based on patient and healthcare professional global assessments of the method of pain control. The SSTS was generally well tolerated, safety parameters, vital signs and adverse event profile typical of that of other opioids and generally similar to that of placebo. Conclusions These results suggest that SSTS is effective and safe for the management of postoperative pain in patients following open abdominal surgery. By virtue of its preprogrammed, noninvasive design, the SSTS avoids the risk of pump programming errors and other complications (e.g. infections and analgesic gaps) that can occur with IV-PCA technology; it also imposes less restriction on postoperative mobility.
Article
Pharmacogenomics (PGx) is the study of how individuals' personal genotypes may affect their responses to various pharmacologic agents. The application of PGx principles in perioperative medicine is fairly novel. Challenges in executing PGx programs into health care systems include physician buy-in and integration into usual clinical workflow, including the electronic health record. This article discusses the current evidence highlighting the potential of PGx with various drug categories (including opioids, nonopioid analgesics, sedatives, β-blockers, antiemetics, and anticoagulants) used in the perioperative process and the challenges of integrating PGx into a health care system and relevant workflows.
Article
Full-text available
Genetic variation in melanocortin-1 receptor (MC1R) has a known role in red hair. Studies on responses to noxious stimuli in red-haired individuals have also been conducted, with mixed findings. To investigate a possible divergence between variants responsible for red hair and pain sensitivity, we performed a gene-wide association analysis in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) cohort. All genotyped (17) MC1R variants were tested for association with heat pain temporal summation and sensitivity. Our analyses showed an association for pain sensitivity with the 5'-UTR, tagged by rs3212361, and one missense variant, rs885479 (R163Q), previously shown to be weakly associated with red hair. For both variants, the minor allele was protective. These results were validated in the 500,000-person U.K. Biobank (UKBB) cohort, where the minor alleles of rs3212361 and rs885479 were associated with a reduced count of persistent pain conditions as well as individual pain conditions. Haplotype association analysis revealed a possible joint effect from the two individual variants. The 5'-UTR variant rs3212361 was further identified as an expression quantitative trait locus (eQTL), associated with reduced transcript levels of MC1R in the brain and in the peripheral tibial nerve. Hair colour association analysis of the loss-of-function 5'-UTR rs3212361 allele identified association with red hair, and red hair colour itself was associated with a reduced count of persistent pain conditions. Together, our results suggest that primarily different mechanisms - affecting expression levels versus protein activity - mediated by different genetic variants in the MC1R locus contribute to red hair and pain.
Chapter
Inhaled anesthetics as single agents provide all of the essential features of general anesthesia, including amnesia, unconsciousness, and immobility. Each of these components results from agent-specific actions on distinct neuronal pathways in the central nervous system. The characteristic immobilizing effect of volatile anesthetics involves a site in the spinal cord. Amnesia and unconsciousness involve incompletely understood supraspinal mechanisms. The precise mechanisms by which inhaled anesthetics alter synaptic transmission have not been fully elucidated despite a number of promising candidate molecular targets. The typical anesthetic binding site is hydrophobic and amphipathic. In contrast to intravenous anesthetics, inhaled anesthetics can act at a number of membrane bound ion channels and receptors at clinically relevant effect-site concentrations. Volatile anesthetics have potentiating effects on inhibitory GABAA and glycine receptors and K⁺ channels, and inhibitory effects on excitatory Na⁺ and Ca²⁺ channels. The gaseous anesthetics nitrous oxide and xenon have predominant NMDA-type glutamate receptor blocking effects. Inhaled anesthetics have a diverse range of clinically significant effects on multiple organ systems, both beneficial and potentially adverse. Potentially beneficial effects include organ protection, while adverse effects include respiratory and cardiovascular depression. Inhaled anesthetics have agent-specific pharmacologic, pharmacokinetic, and side-effect profiles that determine their optimal clinical applications based on patient and procedure specific applications. Anesthetic-induced neurotoxicity occurs in animal models at critical periods in early brain development with unclear clinical significance.
Article
Pharmacogenomics (PGx) is the study of how individuals’ personal genotypes may affect their responses to various pharmacologic agents. The application of PGx principles in perioperative medicine is fairly novel. Challenges in executing PGx programs into health care systems include physician buy-in and integration into usual clinical workflow, including the electronic health record. This article discusses the current evidence highlighting the potential of PGx with various drug categories (including opioids, nonopioid analgesics, sedatives, β-blockers, antiemetics, and anticoagulants) used in the perioperative process and the challenges of integrating PGx into a health care system and relevant workflows.
Conference Paper
Full-text available
Background and Objective This study evaluates the efficacy and safety of a sufentanil sublingual tablet system (SSTS) for the management of postoperative pain following open abdominal surgery (1). Based on the results of three phase III studies, the SSTS has been approved in the EU for the management of acute moderate to severe postoperative pain in adults in a hospital setting. Methods Patients undergoing major abdominal surgery were included from the General Surgical Unit of the Regina Apostolorum Hospital. Patients following surgery with pain intensity of greater than 4 and smaller than 8 on an 11-point numerical rating scale were randomized to receive SSTS dispensing a 15-μg sufentanil tablet sublingually with a 20-minute lockout. Elegible patients met the following criteria: adults older than 18 yr scheduled for major abdominal surgery, ASA 1-3, general anaesthesia or spinal anahestesia (without using intratecal opioids); Exclusion criteria included : ASA ˃ 3, patients with OSAS, or unable to understand the use of SSTS, patients with story of alcoholism or drug dependence. Patients were observed at regular intervals during a 72-hour evaluation period. Numeric Rating Scale ( NRS ) scores were used to assess analgesia and satisfaction with therapy. The primary end point was time-weighted summed pain intensity difference (SPID) over 48 hours. Secondary end points included SPID and total pain relief (TOTPAR) for up to 72 hours and patient and health care provider global assessments of the method of pain control. Results The SSTS was associated with a more rapid onset of analgesia and higher rates of success, based on patient and healthcare professional global assessments of the method of pain control. The SSTS was generally well tolerated, safety parameters, vital signs and adverse event profile typical of that of other opioids and generally similar to that of placebo. Conclusions These results suggest that SSTS is effective and safe for the management of postoperative pain in patients following open abdominal surgery. By virtue of its preprogrammed, noninvasive design, the SSTS avoids the risk of pump programming errors and other complications (e.g. infections and analgesic gaps) that can occur with IV-PCA technology; it also imposes less restriction on postoperative mobility.
Article
Emerging evidence suggests that some phenotypic features, such as eye or hair colour, might predict pain. We investigated if light and dark eye and hair colour would influence pain in 60 healthy subjects divided in groups of 15 according to their eye–hair colour and gender. Pressure pain thresholds (PPTs), cold pressor test (CPT), and quality of the perceived pain were assessed. Findings indicated that dark pigmentation phenotype is more sensitive in response to CPT.
Article
Full-text available
Melanin pigmentation protects the skin from the damaging effects of ultraviolet radiation (UVR). There are two types of melanin, the red phaeomelanin and the black eumelanin, both of which are present in human skin. Eumelanin is photoprotective whereas phaeomelanin, because of its potential to generate free radicals in response to UVR, may contribute to UV-induced skin damage. Individuals with red hair have a predominance of phaeomelain in hair and skin and/or a reduced ability to produce eumelanin, which may explain why they fail to tan and are at risk from UVR. In mammals the relative proportions of phaeomelanin and eumelanin are regulated by melanocyte stimulating hormone (MSH), which acts via its receptor (MC1R), on melanocytes, to increase the synthesis of eumelanin and the product of the agouti locus which antagonises this action. In mice, mutations at either the MC1R gene or agouti affect the pattern of melanogenesis resulting in changes in coat colour. We now report the presence of MC1R gene sequence variants in humans. These were found in over 80% of individuals with red hair and/or fair skin that tans poorly but in fewer than 20% of individuals with brown or black hair and in less than 4% of those who showed a good tanning response. Our findings suggest that in humans, as in other mammals, the MC1R is a control point in the regulation of pigmentation phenotype and, more importantly, that variations in this protein are associated with a poor tanning response.
Article
Full-text available
The presence of both pro-opiomelanocortin-derived peptides and melanocortin (MC) receptors in nociception-associated areas in the spinal cord suggests that, at the spinal level, the MC system might be involved in nociceptive transmission. In the present study, we demonstrate that a chronic constriction injury (CCI) to the rat sciatic nerve, a lesion that produces neuropathic pain, results in changes in the spinal cord MC system, as shown by an increased binding of (125)I-NDP-MSH to the dorsal horn. Furthermore, we investigated whether intrathecal administration (in the cisterna magna) of selective MC receptor ligands can affect the mechanical and cold allodynia associated with the CCI. Mechanical and cold allodynia were assessed by measuring withdrawal responses of the affected limb to von Frey filaments and withdrawal latencies upon immersion in a 4.5 degrees C water bath, respectively. We show that treatment with the MC receptor antagonist SHU9119 has a profound anti-allodynic effect, suggesting that the endogenous MC system has a tonic effect on nociception. In contrast, administration of the MC4 receptor agonists MTII and d-Tyr-MTII primarily increases the sensitivity to mechanical and cold stimulation. No antinociceptive action was observed after administration of the selective MC3 receptor agonist Nle-gamma-MSH. Together, our data suggest that the spinal cord MC system is involved in neuropathic pain and that the effects of MC receptor ligands on the responses to painful stimuli are exerted through the MC4 receptor. In conclusion, antagonism of the spinal melanocortin system might provide a new approach in the treatment of neuropathic pain.
Article
Full-text available
Sex specificity of neural mechanisms modulating nociceptive information has been demonstrated in rodents, and these qualitative sex differences appear to be relevant to analgesia from kappa-opioid receptor agonists, a drug class reported to be clinically effective only in women. Via quantitative trait locus mapping followed by a candidate gene strategy using both mutant mice and pharmacological tools, we now demonstrate that the melanocortin-1 receptor (Mc1r) gene mediates kappa-opioid analgesia in female mice only. This finding suggested that individuals with variants of the human MC1R gene, associated in our species with red hair and fair skin, might also display altered kappa-opioid analgesia. We found that women with two variant MC1R alleles displayed significantly greater analgesia from the kappa-opioid, pentazocine, than all other groups. This study demonstrates an unexpected role for the MC1R gene, verifies that pain modulation in the two sexes involves neurochemically distinct substrates, and represents an example of a direct translation of a pharmacogenetic finding from mouse to human.
Article
Full-text available
Differences in skin and hair color are principally genetically determined and are due to variation in the amount, type, and packaging of melanin polymers produced by melanocytes secreted into keratinocytes. Pigmentary phenotype is genetically complex and at a physiological level complicated. Genes determining a number of rare Mendelian disorders of pigmentation such as albinism have been identified, but only one gene, the melanocortin 1 receptor (MCR1), has so far been identified to explain variation in the normal population such as that leading to red hair, freckling, and sun-sensitivity. Genotype-phenotype relations of the MC1R are reviewed, as well as methods to improve the phenotypic assessment of human pigmentary status. It is argued that given advances in model systems, increases in technical facility, and the lower cost of genotype assessment, the lack of standardized phenotype assessment is now a major limit on advance.
Article
Full-text available
Age and body temperature alter inhalational anesthetic requirement; however, no human genotype is associated with inhalational anesthetic requirement. There is an anecdotal impression that anesthetic requirement is increased in redheads. Furthermore, red hair results from distinct mutations of the melanocortin-1 receptor. Therefore, the authors tested the hypothesis that the requirement for the volatile anesthetic desflurane is greater in natural redheaded than in dark-haired women. The authors studied healthy women with bright red (n = 10) or dark (n = 10) hair. Blood was sampled for subsequent analyses of melanocortin-1 receptor alleles. Anesthesia was induced with sevoflurane and maintained with desflurane randomly set at an end-tidal concentration between 5.5 and 7.5%. After an equilibration period, a noxious electrical stimulation (100 Hz, 70 mA) was transmitted through bilateral intradermal needles. If the volunteer moved in response to stimulation, desflurane was increased by 0.5%; otherwise, it was decreased by 0.5%. This was continued until volunteers "crossed over" from movement to nonmovement (or vice versa) four times. Individual logistic regression curves were used to determine desflurane requirement (P50). Desflurane requirements in the two groups were compared using Mann-Whitney nonparametric two-sample test; P < 0.05 was considered statistically significant. The desflurane requirement in redheads (6.2 vol% [95% CI, 5.9-6.5]) was significantly greater than in dark-haired women (5.2 vol% [4.9-5.5]; P = 0.0004). Nine of 10 redheads were either homozygous or compound heterozygotes for mutations on the melanocortin-1 receptor gene. Red hair seems to be a distinct phenotype linked to anesthetic requirement in humans that can also be traced to a specific genotype.
Article
Full-text available
The purpose of this study is to evaluate both painless and painful sensory transmission in patients with Complex Regional Pain Syndrome (CRPS) using the automated electrodiagnostic sensory Nerve Conduction Threshold (sNCT) test. This test generates reliable, painless Current Perception Threshold (CPT) and atraumatic Pain Tolerance Threshold (PTT) measures. Standardized CPT and PTT measures using constant alternating current sinusoid waveform stimulus at 3 different frequencies 5 Hz, 250 Hz, and 2 kHz (Neurometer CPT/C Neurotron, Inc. Baltimore, MD) were obtained from CRPS subjects at a distal phalange of the affected extremity and at an ipsilateral asymptomatic control site. Matched sites were tested on healthy subjects. Detection sensitivities for an abnormal PTT and CPT test were calculated based on specificity of 90% as determined from data obtained from healthy controls. A Spearman rank correlation was used to test for a significant association between presence of allodynia and an abnormal PTT or CPT at any frequency tested. Thirty-six CRPS subjects and 57 healthy controls were tested. The highest detection sensitivity of the PTT test from symptomatic test sites was 63% for the finger and 71% for the toe. PTT abnormalities were also detected, to a lesser degree, at the asymptomatic control site (41% finger control site, 16% toe control site). The highest CPT detection sensitivity at the symptomatic site was 37% for the finger site and 53% for the toe site. CPT abnormalities were also detected at the asymptomatic control site (29% finger control site, 37% toe control site). Eighty-six percent of the CRPS subjects had either a PTT or CPT abnormality at any frequency at the symptomatic site. There was a significant correlation between presence of allodynia and presence of an abnormal CPT and PTT, respectively (P < .01). The correlation coefficient was lower for CPT than for PTT, ie, 0.34 versus 0.6 for the finger and 0.48 versus 0.67 for the toe, respectively. In studied CRPS patients an abnormal PTT was detected with higher sensitivity than an abnormal CPT. Assessing PTT may become a useful electrodiagnostic quantitative sensory test for diagnosing and following the course of neuropathic pain conditions.
Article
`Do freckles and red hair help Irishmen catch leprechauns?'1 There are at least two reasons for being interested in the biology of hair and skin colour. First, variation in skin and hair colour is perhaps the most polymorphic of all visible differences between humans, and has historically been of profound social importance. We get used to seeing little people—they are called children—whereas even the most liberal parent shows concern when children start verbalizing their classification of human skin colours. It is likely that the influence of differences in pigmentation rivals or exceeds that of infectious diseases on human history. Second, variation in pigmentation is the most important risk factor for the major forms of skin cancer, both melanoma, and basal and squamous cell carcinoma.2,3 If one were to collect a random sample of people from around the world, their constitutional risk of developing skin cancer would vary over 100-fold, and most of this would be attributable to differences in skin colour.4,5 The interaction of skin colour and ultraviolet radiation provides a timely reminder of the difficulties of viewing nature and nurture as anything but contingent: to an epidemiologist, ultraviolet radiation is the major determinant of skin cancer, whereas for a geneticist, pigment, predominantly under genetic control, is the major determinant. Both views are of course correct. Of course in between the two reasons given above lie a host of interesting biological questions. Can we explain the variation in human pigmentation solely in terms of protecting against ultraviolet radiation, or alternatively do we imagine that natural selection is only part of the explanation. Why are the Scandinavians taller and blond and the Irish more often red-haired? Is this all natural selection at work, or is there an element of assortive mating depending on choice …
Article
The adjustment of local anesthetic dosage for peripheral nerve block must meet two basic requirements: a drug concentration sufficient to inhibit Na+ channels to the point of impulse failure and a volume of drug sufficient to expose a length of nerve longer than the "critical length" for propagation failure. This study examines the lidocaine dosage requirement, in milligrams, for functionally assayed sciatic nerve block in the rat using a fourfold range of volume corresponding to concentrations from 2 to 7 mg/ml and compares these blocks with the intraneural lidocaine content after injection of equipotent doses. Lidocaine was injected percutaneously at the sciatic nerve in volumes of 0.05 ml, 0.1 ml, and 0.2 ml (all at pH 6.8), and quantitative neurobehavioral assays were conducted on male Sprague-Dawley rats weighing from 200 to 250 g. The dose requirements for 50% maximum possible effect (ED50) and for just achieving complete block (i.e., minimal blocking dose for 90% effect), the fraction of completely blocked animals, and the duration of complete block at all doses were assessed for the inhibition of three different functions: proprioception, motor, and nocifensive activities. Radiolabeled (14C) lidocaine was injected in separate experiments, and the total drug content and its longitudinal distribution were determined in nerves dissected from animals (sevoflurane anesthetized) at 10 min, the time of peak block, after injection of the E50 and minimal blocking dose for 100% effect for the three different volumes. For all functions, the smaller the volume, the lower was the E50, resulting in a nearly constant concentration to achieve an equivalent degree of block. Durations of block were longer, and the dose to full block was lower for the smaller injected volumes. Intraneural lidocaine, at the equipotent doses for analgesia, was not related to concentration but rather increased with increasing volume, being almost proportional to the given dose. The longitudinal spread of lidocaine was also greater with increasing volume of lidocaine solution. Blocks of greater depth and longer duration result from injection of smaller volumes and, correspondingly, higher lidocaine concentrations containing the same dose. The corollary is that lower lidocaine doses are required to achieve the same effect when smaller volumes are injected. Curiously, when the equivalent E50 is injected, total drug taken into the nerve is less from the smaller volumes than from the larger volumes, even though the peak functional effects are equal. Total intraneural local anesthetic may not represent the effective drug in the compartment that contains nerve axons, the actual location of neural blockade.
Article
Impulse block by LA occurs through the inhibition of voltage-gated Na+ channels. Both protonated and neutral LAs can inhibit Na+ channels though interference with the conformational changes that underly the activation process (the sequence of events that occurs as channels progress from the closed resting state to the open conducting state). The occlusion of open channels contributes little to the overall inhibition. Local anesthetic inhibition of Na+ currents increases with repetitive depolarizations in a process called phasic block. Phasic block represents increased LA binding, either because more channels become accessible during depolarization or because the channel conformations favored by depolarization bind LA with higher affinity. The details of phasic block are dependent on LA chemistry: certain LAs bind and dissociate quite rapidly, others act more slowly; some LAs interact effectively with closed states that occur intermediately between resting and open states, others favor the open channel, and still others have a higher affinity for inactivated states. Channel activation accelerates LA binding, and LAs may bind more tightly to activated and inactivated than to resting channels. In this regard, both the modulated receptor and the guarded receptor hypotheses are valid. In binding to activated and inactivated channels, LAs prevent the conformational changes of activation and antagonize the binding of activator agents that poise channels in activated, open states. These reciprocal actions are one aspect of the concerted conformational rearrangements that occur throughout Na+ channels during gating. The LA binding site may exist in the channel's pore, at the membrane-protein interface, or within the protein subunits of the channel. Judging from its susceptibility to intracellular proteases and its accessibility to LAs with limited membrane permeability (i.e., quaternary LAs in the cytoplasm), the site lies nearer to the cytoplasmic than the external surface of the membrane. Nevertheless, protons in the external medium influence the dissociation of LA from the closed channel. Binding of LAs at the inhibitory site is weak and loose. If one accounts for the membrane-concentrating effects of LA hydrophobicity that are expressed as membrane: buffer partition coefficients equal to 10(2)-10(4), then the apparent LA affinities are low. The equilibrium dissociation constants calculated on the basis of free drug in the membrane are 1-10 mM, with a correspondingly weak binding to the inhibitory LA site. The stereospecificity of LA action is also relatively nonselective, suggesting a loose fit between ligand and binding site.(ABSTRACT TRUNCATED AT 400 WORDS)
Article
Nerve conduction velocities (NCVs) are the standard measurements used to confirm the presence or absence of diabetic neuropathy. NCVs were contrasted with the newer technique of measurement of alternating current perception thresholds (CPTs) in assessing the quantitative level of correlation with severity of diabetic sensory neuropathy. A very detailed, scored neurological history (symptoms) and physical examination, emphasising sensory assessment, was conducted on 71 individuals with diabetic neuropathy of varying degrees of severity. Sensory and motor NCVs and CPTs at 5, 250, and 2000 Hz of the upper and lower extremities were determined for these individuals. In addition, vibration thresholds (VTs) were measured as a third modality. Twenty eight individuals underwent repeated evaluations at 2, 6, 10 and 12 months after the initial procedures. Using the results of 169 complete evaluations, correlations were determined between physical scores (PS) and symptoms scores (SS) and NCVs. NCV correlations with the SS were weaker than with the PS. The strongest of the correlations were found between the PS and motor NCVs of the median nerve (rho = 0.29) and the tibial nerve (rho = 0.38). Normal NCVs were present in the face of very significant historical and physical abnormality. Correlations of the SS and PS with both VTs and CPTs were higher than with the NCVs. CPTs proved the more effective as predictors of both symptomatic and physical impairment. NCVs appear to lack the resolving power necessary to evaluate subtle differences in clinical state of diabetic sensory neuropathy. The supplementary use of current perception testing may improve the quantitative assessment of this condition.
Article
Recent technology allows for quantitative and selective measurement of A beta, A delta, and C fiber nerve transmission. To gain further insight into the physiology of differential block after lidocaine spinal anesthesia, the function of these different fibers was quantitatively measured over time, and these measurements were correlated with regression of anesthesia to pinprick, touch, cold, and tolerance of tetanic electrical current (equivalent to surgical incision). Six volunteers received lidocaine spinal anesthesia with 50 mg lidocaine (5% in dextrose). Cutaneous current perception thresholds at 2,000, 250, and 5 Hz, which stimulate A beta, A delta, and C fibers, respectively, were determined at L2-L3 (medial aspect above knee) before and every 10 min after spinal anesthesia. Dermatomal levels to pinprick, touch, and cold were assessed every 5 min after spinal anesthesia. Tolerance to tetanic electrical stimulus was assessed at L2-L3 every 10 min after spinal anesthesia. Differential block was demonstrated by the sequential return of sensation to touch, pinprick, and cold at L2-L3. Recovery of function of A beta, A delta, and C fibers correlated with return of sensation to touch (R2 = 0.7, p = 0.03), pinprick (R2 = 0.75, p = 0.02), and cold (R2 = 0.67, p = 0.04) respectively. Loss of tolerance of surgical anesthesia corresponded to return of A beta current perception thresholds to baseline, whereas current perception thresholds for A delta and C fibers were still increased to greater than baseline (p = 0.025). Differential sensory block during spinal anesthesia is due to different recovery profiles of A beta, A delta, and C fibers. Return of A beta current perception thresholds to baseline correlated with duration of surgical anesthesia as assessed with an electrical stimulation model.
Article
Is a person's response to one noxious stimulus similar to his/her responses to other noxious stimuli? This long-investigated topic in pain research has provided inconclusive results. In the present study, 2 samples were studied: one using 60 healthy volunteers and the other using 29 patients with coronary artery disease. Results showed near-zero correlations between measures of heat, cold, ischemic, and electrical laboratory pains, as well as between these laboratory pains and an idiopathic pain, the latency to exercise-induced angina in the patients. Power analyses showed that the sample sizes were sufficient to detect a correlation of 0.50 or greater at the 0.05 level 99% of the time in the healthy volunteers, and between 80 and 85% of the time in the patients. Reliability analyses indicated retest correlations on the order of 0.60 for these measures, indicating that the lack of correlation between modalities was not due to unreliability within a measure. These studies fail to demonstrate alternate-forms reliability among these tests, and also fail to support the notion that a person can be characterized as generally stoical or generally complaining to any painful stimulus. In practice, this implies that a battery of tests should generally be used to assess pain sensitivity and also that assessments of one pain modality are not generally useful for making inferences about another.
Article
Sodium ion (Na+) channels, which initiate the action potential in electrically excitable cells, are the molecular targets of local anesthetic drugs. Site-directed mutations in transmembrane segment S6 of domain IV of the Na+ channel alpha subunit from rat brain selectively modified drug binding to resting or to open and inactivated channels when expressed in Xenopus oocytes. Mutation F1764A, near the middle of this segment, decreased the affinity of open and inactivated channels to 1 percent of the wild-type value, resulting in almost complete abolition of both the use-dependence and voltage-dependence of drug block, whereas mutation N1769A increased the affinity of the resting channel 15-fold. Mutation I1760A created an access pathway for drug molecules to reach the receptor site from the extracellular side. The results define the location of the local anesthetic receptor site in the pore of the Na+ channel and identify molecular determinants of the state-dependent binding of local anesthetics.
Article
The localization of the melanocortin 1 (MC1) receptor in brain was investigated by in situ hybridization and immunohistochemistry. In rat periaqueductal gray matter (PAG), a small number of cells which displayed a punctate distribution showed a specific hybridization signal for MC1 receptor mRNA, whereas other regions studied were negative. In human PAG, the immunoreactivity for MC1 receptor was detected in scattered cells. These results indicate that a restricted distribution of MC1 receptor is present in the central nervous system.
Article
Distribution of cDNA for five individual melanocortin receptor subtypes in 20 different human tissues was determined by PCR using subtype specific primers. PCR products were first visualised by agarose gel electrophoresis and ethidium bromide staining, and specific products were identified for melanocortin 1 receptor (MC1R) in pituitary and testis, for MC2R in adrenal gland, for MC3R in heart, for MC5R in adrenal gland, fat cells, kidney, leukocytes, lung, lymph node, mammary gland, ovary, pituitary, testis and uterus. The MC4R cDNA could not be detected by ethidium bromide staining. More tissues were revealed as positive when the DNA from PCR were hybridised with subtype specific radioactive probes. All the subtypes except MC4R could be detected in testis. MC4R could only be detected in pituitary. This is the first report describing the comprehensive distribution analysis of melanocortin receptor subtype cDNAs in human tissues, and provides a link between individual receptor subtype and diverse biological activities of melanocortic peptides in the respective target tissues.
Article
Behavioral nociceptive responses evoked by relatively high rates of noxious radiant skin heating appear to be mediated by A delta nociceptor activation, whereas responses evoked by low rates of skin heating appear to be mediated by the activation of C-fiber nociceptors. This hypothesis was confirmed by the results of single unit recordings of A delta and C nociceptive afferent fibers isolated from the saphenous nerves of pentobarbital anesthetized rats. Heating the hind paw skin of the rat at a relatively high rate of 6.5 degrees C/sec activated A delta units within 2 sec after the onset of the stimulus. This response latency is similar to the 2.5 sec latency of the foot withdrawal response to a similar stimulus. In contrast, C-fibers were only slightly activated at a longer latency of 5-6 sec. Conversely, heating the hind paw skin at a relatively low rate of 0.9 degrees C/sec activated C-fibers, but evoked only a few action potentials in A delta nociceptors. C-fibers began firing at a rate less than 1 Hz between 8 and 10 sec after the onset of heating and fired at a mean rate of 1.5 Hz between 10 and 12 sec, which corresponds to the latency of the foot withdrawal response. Topical application of capsaicin to the hind paw skin decreased the latency of C-fiber responses from control values of 8-12 sec to approximately 4 sec after topical capsaicin treatment. The mean latency of the foot withdrawal response to skin heating at the low rate is also reduced from control values of 12-14 sec to 4-5 sec after capsaicin treatment. In contrast, capsaicin treatment did not significantly affect the responses of A delta nociceptors. These results support the conclusion that nociceptive foot withdrawal responses to a low rate of skin heating are mediated predominantly by the activation of C-fiber nociceptors. These results provide direct evidence that, under the conditions of these experiments, nociceptive foot withdrawal responses evoked by high rates of skin heating are primarily mediated by A delta nociceptors, and foot withdrawal responses evoked by low rates of skin heating are primarily mediated by C-fiber nociceptors.
Article
Findings from both animal and human research suggest that pain sensitivity changes across the menstrual cycle; however, among humans the nature of these menstrual cycle effects remains unclear. The present study used a repeated-measures design to evaluate changes in thermal and ischemic pain responses during three phases of the menstrual cycle, midfollicular (postmenstrual), ovulatory, and mid-to-late luteal (premenstrual), in 11 healthy women. The cycle phase during which subjects began their participation was determined randomly. Plasma levels of estrogen, progesterone, luteinizing hormone (LH), testosterone, and beta-endorphin were determined at each experimental session. Participants also completed a daily diary of physical and emotional symptoms for two complete menstrual cycles before the experimental sessions. The results indicated that women showed less ischemic pain sensitivity during the midfollicular compared with the ovulatory and mid-to-late luteal phases, but thermal pain responses did not vary significantly across menstrual cycle phases. Physical and emotional symptoms were minimal and did not change significantly across the menstrual cycle. These findings indicate greater ischemic but not thermal pain sensitivity among women after the midcycle LH surge. The practical relevance and potential mechanisms of these findings are discussed.
Article
Unlabelled: Local anesthetics suppress excitability by interfering with ion channel function. Ensheathment of peripheral nerve fibers, however, impedes diffusion of drugs to the ion channels and may influence the evaluation of local anesthetic potencies. Investigating ion channels in excised membrane patches avoids these diffusion barriers. We investigated the effect of local anesthetics with voltage-dependent Na+ and K+ channels in enzymatically dissociated sciatic nerve fibers of Xenopus laevis using the patch clamp method. The outside-out configuration was chosen to apply drugs to the external face of the membrane. Local anesthetics reversibly blocked the transient Na+ inward current, as well as the steady-state K+ outward current. Half-maximal tonic inhibiting concentrations (IC50), as obtained from concentration-effect curves for Na+ current block were: tetracaine 0.7 microM, etidocaine 18 microM, bupivacaine 27 microM, procaine 60 microM, mepivacaine 149 microM, and lidocaine 204 microM. The values for voltage-dependent K+ current block were: bupivacaine 92 microM, etidocaine 176 microM, tetracaine 946 microM, lidocaine 1118 microM, mepivacaine 2305 microM, and procaine 6302 microM. Correlation of potencies with octanol:buffer partition coefficients (logP0) revealed that ester-bound local anesthetics were more potent in blocking Na+ channels than amide drugs. Within these groups, lipophilicity governed local anesthetic potency. We conclude that local anesthetic action on peripheral nerve ion channels is mediated via lipophilic drug-channel interactions. Implications: Half-maximal blocking concentrations of commonly used local anesthetics for Na+ and K+ channel block were determined on small membrane patches of peripheral nerve fibers. Because drugs can directly diffuse to the ion channel in this model, these data result from direct interactions of the drugs with ion channels.
Article
The melanocortin 1 receptor is a G-protein-coupled receptor that acts as a control point for control of the eumelanin/phaeomelanin ratio in mouse hair. MC1 receptor loss of function mutations lead to an increase in the ratio of phaeomelanin/eumelanin in many mammals resulting in yellow or red coat colours. We have previously shown that several common point mutations in the human MC1 receptor are overrepresented in North European redheads and in individuals with pale skin. In order to determine the functional significance of these changes we have carried out transfection and binding studies. Expression of the Val60Leu, Arg142His, Arg151Cys, Arg160Trp, and Asp294His receptors in COS 1 cells revealed that these receptors were unable to stimulate cAMP production as strongly as the wild type receptor in response to alpha-melanocyte-stimulating hormone stimulation. None of the mutant receptors displayed complete loss of alphaMSH binding, with only the Arg142His and Asp294His displaying a slight reduction in binding affinity.
Article
The cloning of five different subtypes of melanocortin receptor subtypes have recently opened up new possibilities for the development of drugs. The physiological roles of the five melanocortin receptors have started to become understood, and compounds with selective actions on some of the five subtypes have become available. Presently, most clinically promising application for drugs active on melanocortin receptors are for control of feeding homeostasis and body weight and for treatment of inflammatory diseases. I review here the cloning, localisation, function and structure of the melanocortin receptors, in relation to the possibilities to develop selective drugs for these receptors.
Article
Considerable evidence indicates sex-related differences in pain responses and in the effectiveness of various analgesic agents. Specifically, females are at greater risk for experiencing many forms of clinical pain and are more sensitive to experimentally induced pain relative to males. Regarding analgesic responses, nonhuman animal studies indicate greater opioid analgesia for males, while a limited human literature suggests the opposite. Though the mechanisms underlying these effects remain unclear, the influence of gonadal hormones on nociceptive processing represents one plausible pathway whereby such sex differences could emerge. The present article reviews the complex literature concerning sex steroid effects on pain responses and analgesia. First, nonhuman animal research related to hormonal effects on nociceptive sensitivity and analgesic responses is presented. Next, human studies regarding gonadal hormonal influences on experimental pain responses are reviewed. Several potential mechanisms underlying hormonal effects on nociceptive processing are discussed, including hormonal effects to both peripheral and central nervous system pathways involved in pain transmission. Finally, based on these findings we draw several conclusions and make specific recommendations that will guide future research as it attempts to elucidate the magnitude and importance of sex-related hormonal effects on the experience of pain.
Article
Animal and human studies indicate the existence of important sex-related differences in opioid-mediated behavior. In this study the authors examined the influence of morphine on experimentally induced pain in healthy male and female volunteers. Young healthy men and women (10 of each sex) received intravenous morphine (bolus 0.1-mg/kg dose followed by an infusion of 0.030 mg. kg-1. h-1 for 1 h). Pain threshold and pain tolerance in response to a gradual increase in transcutaneous electrical stimulation, as well as plasma concentrations of morphine and its major metabolites (morphine-6-glucuronide and morphine-3-glucuronide) were determined at regular intervals up to 7 h after the start of morphine infusion. A population pharmacodynamic model was used to analyze the morphine-induced changes in stimulus intensity. The improvement of the model fits by inclusion of covariates (sex, age, weight, lean body mass) was tested for significance. The model is characterized by baseline current, a rate constant for equilibrium between plasma and effect-site morphine concentrations (ke0), and analgesic potency (AC50, or the morphine concentration causing a 100% increase in stimulus intensity for response). The inclusion of the covariates age, weight, and lean body mass did not improve the model fits for any of the model parameters. For both pain threshold and tolerance, a significant dependency on sex was observed for the parameters ke0 (pain threshold: 0.0070 +/- 0.0013 (+/- SE) min-1 in men vs. 0.0030 +/- 0. 0005 min-1 in women; pain tolerance: 0.0073 +/- 0.0012 min-1 in men vs. 0.0024 +/- 0.0005 min-1 in women) and AC50 (pain threshold: 71.2 +/- 10.5 nm in men vs. 41.7 +/- 8.4 nm in women; pain tolerance: 76. 5 +/- 7.4 nm in men vs. 32.9 +/- 7.9 nm in women). Baseline currents were similar for both sexes: 21.4 +/- 1.6 mA for pain threshold and 39.1 +/- 2.3 mA for pain tolerance. Concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide did not differ between men and women. These data show sex differences in morphine analgesia, with greater morphine potency but slower speed of onset and offset in women. The data are in agreement with observations of sex differences in morphine-induced respiratory depression and may explain higher postoperative opioid consumption in men relative to women.
Article
The melanocortins are a family of bioactive peptides derived from proopiomelanocortin, and share significant structural similarity. Those peptides are best known for their stimulatory effects on pigmentation and steroidogenesis. Melanocortins are synthesized in various sites in the central nervous system and in peripheral tissues, and participate in regulating multiple physiological functions. Research during the past decade has provided evidence that melanocortins elicit their diverse biological effects by binding to a distinct family of G protein-coupled receptors with seven transmembrane domains. To date, five melanocortin receptor genes have been cloned and characterized. Those receptors differ in their tissue distribution and in their ability to recognize the various melanocortins and the physiological antagonists, agouti signaling protein and agouti-related protein. These advances have opened new horizons for exploring the significance of melanocortins, their antagonists, and their receptors in a variety of important physiological functions.
Article
Considerable experimental research suggests that ovarian hormones can influence pain perception, and recent epidemiologic and clinical research suggests that exogenous hormone use may influence the prevalence and severity of clinical pain among women. However, to date no studies have examined the influence of hormone replacement therapy (HRT) on experimental pain responses and recent pain complaints among postmenopausal women. In this study, self-reported recent pain and general health were obtained, and thermal pain responses were assessed in three groups of healthy older adults: (1) women on HRT, (2) women not on HRT (No-HRT), and (3) men. Results indicated no group differences in recent pain complaints or self-reported health, but differences emerged for measures of thermal pain perception. Specifically, HRT women showed lower pain thresholds and tolerances than No-HRT women and men, and the latter two groups did not differ from each other. The potential explanations and limitations of the observed findings are discussed.
Article
Red hair in humans is associated with variant alleles of the alphaMSH receptor gene, MC1R. Loss of MC1R function in other mammals results in red or yellow hair pigmentation. We show that a mouse bacterial artificial chromosome (BAC) which contains Mc1r will efficiently rescue loss of Mc1r in transgenic mice, and that overexpression of the receptor suppresses the effect of the endogenous antagonist, agouti protein. We engineered the BAC to replace the mouse coding region with the human MC1R sequence and used this in the transgenic assay. The human receptor also efficiently rescued Mc1r deficiency, and in addition, appeared to be completely resistant to the effects of agouti, suggesting agouti protein may not play a role in human pigmentary variation. Three human variant alleles account for 60% of all cases of red hair. We engineered each of these in turn into the BAC and find that they have reduced, but not completely absent, function in transgenic mice. Comparison of the phenotypes of alphaMSH-deficient mice and humans in conjunction with this data suggests that red hair may not be the null phenotype of MC1R.
Article
Unlabelled: We used a neuroselective transcutaneous electrical stimulus to determine the onset time of cutaneous anesthesia with 4% liposomal lidocaine under occluded and nonoccluded conditions. The pain tolerance threshold (PTT) was used to atraumatically evaluate nociception. Twenty adult volunteers had liposomal lidocaine applied to the volar surface of each forearm for durations ranging from 0 through 30 min (at 5-min intervals) under occluded and nonoccluded conditions. The PTT was determined using three different frequencies (2000 Hz, 250 Hz, 5 Hz) stimulating A beta, A delta, and C fibers, respectively. The time to reach the maximum PTT achieved defined the anesthetic onset time for each frequency. A differential onset of cutaneous anesthesia among the three frequencies was clearly demonstrated, however there was no significant difference in onset time between occluded and nonoccluded conditions. Blockade of C fiber transmission occurred significantly earlier than that of A delta (P = 0.029), which occurred earlier than that of A beta (P = 0.001) as determined using the Wilcoxon's signed rank test. We conclude that a mean onset time of approximately 4 +/- 2 min for blockade of C fiber transmission and 6 +/- 4 min for A delta fiber transmission suggests that painful stimuli such as venipuncture may be attenuated as early as 7 min. Implications: An average onset time of approximately 7 min for topical 4% liposomal lidocaine was determined using neuroselective neurostimulation. This suggests that procedural pain such as venipuncture may be attenuated in this time frame. This technique requires correlation with conventional sensory measurements.
Article
Several studies indicate that females are more sensitive to experimentally induced pain than males. Moreover, it was recently shown that temporal summation of heat pain is greater in females than males, suggesting that central processing of nociceptive input may be upregulated in women. Temporal summation of pain has been examined principally using thermal or electrical stimuli. The purpose of this study was to investigate the temporal summation to noxious mechanical stimulation, and examine gender differences in temporal summation of mechanically evoked pain. A sharp probe was used to apply brief mechanical stimuli on the fingers of ten healthy females and ten healthy males. Trains of ten repetitive stimuli were applied at an intensity of 1.2-1.3 x the individual subject's pain threshold, at interstimulus intervals (ISIs) ranging from 1 to 6 s. The same or different skin sites were stimulated in any single train of stimuli. The pain ratings for the fifth as well as the tenth stimulus were significantly higher than those for the first stimulus. Also, the pain responses for the tenth stimulus were higher than those for the fifth. There was no overall gender difference in pain ratings, however, there was a significant trial # x gender interaction. Males and females provided comparable magnitude estimates for the first stimulus in the train, but females provided higher pain ratings than males for the fifth as well as the tenth stimulus. Temporal summation occurred across all ISIs, but shorter ISIs (1-3 s) elicited significantly greater temporal summation than longer ISIs (4-6 s). Finally, although higher pain ratings were obtained when the ten consecutive stimuli were applied on the same versus different skin areas, the degree of temporal summation was not significantly different. These findings indicate that temporal summation of mechanically evoked pain is higher in females compared to males, is stimulation frequency dependent and is centrally mediated.
Article
Research consistently indicates that gender differences exist in pain perception, with females typically reporting more negative responses to pain than males. It also seems as if males and females use and benefit from different coping strategies when under stress; females seem to prefer emotion-focused coping, whereas males prefer sensory-focused coping. Unfortunately, experimental research that examines such differences in the context of pain has not yet been adequately investigated. The aim of the current study was, therefore, to determine whether gender differences would be found in the effect that sensory-focused and emotion-focused coping instructions have on cold pressor pain experiences. Participants consisted of 24 male and 26 female healthy adults, all of whom reported no current pain. A consistent pattern of effects was found, over both behavioural and self-report measures of pain. Compared to females, males exhibited less negative pain responses when focusing on the sensory component of pain (i.e. increased threshold, tolerance and lower sensory pain). Furthermore, compared to sensory focusing, emotional focusing was found to increase the affective pain experience of females. Together these results confirm that important differences exist between men and women in the effects pain coping instructions have on the experience of pain. The implications of such findings for research and practice are discussed.
Article
We assessed the influence of changes in steroid hormones across the menstrual cycle on the spinal nociceptive reflex. We studied in 14 healthy women during the follicular and luteal phase the nociceptive flexion reflex (RIII reflex), an objective neurophysiological method that allows exploring possible abnormal functioning of the pain-control system. The basal body temperature (BBT) was used to evaluate the different phases of the ovarian cycle. The menstrual distress questionnaire (MDQ) was also applied for monitoring somatic and psychological symptoms during the cycle. During the luteal phase, the threshold of the RIII reflex (Tr) and the psychophysical threshold for pain (Tp) were both significantly reduced compared with the follicular phase. Moreover, the reflex threshold in the luteal phase was negatively correlated to the total MDQ score of the recording day. A higher sensitivity to pain stimuli was observed during the luteal phase of the menstrual cycle, which probably results from a reduction in the inhibitory descending control on spinal nociceptive flexion reflex. Complex neuromodulatory interactions of ovarian steroids with other systems of neurotransmission (especially serotonergic) may account for these observations.
Article
Our objective was to quantify the extent and time course of the effects of morphine-6-glucuronide and morphine on pain threshold, pain tolerance, pupil diameter, and side effects. In a double-blind, placebo-controlled, randomized, 3-way crossover study, 12 healthy volunteers (6 men and 6 women) received 63 to 112 mg of morphine-6-glucuronide or 26 to 66 mg of morphine as an intravenous bolus, followed by an infusion of the same medication for 1.8 to 6.4 hours. Analgesia was assessed every 30 minutes for up to 16 hours by means of transcutaneous electrical stimulation (sine wave, 5 Hz; intensity, 0-9.99 mA). Pupil diameter and side effects were recorded concomitantly. At the administered doses, morphine-6-glucuronide and morphine had comparable effects on pain tolerance, pupil diameter, and side effects. The delay between the time course of the plasma concentrations and the time course of the effects was longer for morphine-6-glucuronide than for morphine (transfer half-life, 8.2 hours versus 2.6 hours for pain tolerance and 7.7 hours versus 2.8 hours for pupil diameter). The slope of the linear concentration versus effect relationship for pain tolerance was flatter for morphine-6-glucuronide than for morphine (0.05% versus 0.6% increase in pain tolerance per nanomole per liter of morphine-6-glucuronide and morphine at effect site, respectively). Morphine-6-glucuronide was less potent than morphine in producing pupil constriction (mean concentration at half-maximum effect, 745 nmol/L versus 26.4 nmol/L for morphine-6-glucuronide and morphine, respectively). In carriers of the mutated G118 allele of the mu-opioid receptor, the potency of the pupil-constricting effects of morphine-6-glucuronide and morphine was significantly smaller, and carriers of the G118 allele reported less nausea and vomited less often after administration of morphine-6-glucuronide. Morphine-6-glucuronide clearly produced analgesic effects in healthy volunteers. However, the high amounts of systemic morphine-6-glucuronide needed to produce the same effects as morphine suggest that morphine-6-glucuronide barely contributes to the central nervous opioid effects after administration of analgesic doses of morphine.
Article
We have examined MC1R variant allele frequencies in the general population of South East Queensland and in a collection of adolescent dizygotic and monozygotic twins and family members to define statistical associations with hair and skin color, freckling, and mole count. Results of these studies are consistent with a linear recessive allelic model with multiplicative penetrance in the inheritance of red hair. Four alleles, D84E, R151C, R160W, and D294H, are strongly associated with red hair and fair skin with multinomial regression analysis showing odds ratios of 63, 118, 50, and 94, respectively. An additional three low-penetrance alleles V60L, V92M, and R163Q have odds ratios 6, 5, and 2 relative to the wild-type allele. To address the cellular effects of MC1R variant alleles in signal transduction, we expressed these receptors in permanently transfected HEK293 cells. Measurement of receptor activity via induction of a cAMP-responsive luciferase reporter gene found that the R151C and R160W receptors were active in the presence of NDP-MSH ligand, but at much reduced levels compared with that seen with the wild-type receptor. The ability to stimulate phosphorylation of the cAMP response element binding protein (CREB) transcription factor was also apparent in all stimulated MC1R variant allele-expressing HEK293 cell extracts as assessed by immunoblotting. In contrast, human melanoma cell lines showed wide variation in the their ability to undergo cAMP-mediated CREB phosphorylation. Culture of human melanocytes of known MC1R genotype may provide the best experimental approach to examine the functional consequences for each MC1R variant allele. With this objective, we have established more than 300 melanocyte cell strains of defined MC1R genotype.
Article
Unlabelled: We evaluated the effect of transdermal lidocaine on differential sensory nerve block in 15 healthy volunteers. Lidocaine 10% gel was applied topically to a forearm and covered with a plastic film. Three types of sensory nerve fibers (Abeta, Adelta, and C fibers) were evaluated with a series of 2000-, 250-, and 5-Hz stimuli using current perception threshold (CPT) testing. Sensations of touch, pinprick, cold, and warmth were also measured. These measurements were made before the topical lidocaine (baseline), 60 min after the draping (T0), and at 1-h intervals until 5 h after T0 (T1 to T5). A significant increase in CPT compared with baseline was observed until T2 at 5 Hz and T4 at 250 Hz, whereas the increase in CPT at 2000 Hz continued throughout the study period. All subjects experienced the disappearance of pinprick and cold sensations, whereas touch and warmth sensations were detectable during the study period. We conclude that when lidocaine is applied transdermally, the sensitivity of nerves to local anesthetics is proportional to the axon diameters. However, pinprick and cold sensation are affected more strongly than other sensations at receptor sites. Implications: We evaluated the effect of transdermal lidocaine on differential sensory nerve block in healthy volunteers. Our results show that the sensitivity of nerves to local anesthetics is proportional to the axon diameter.
Article
Accumulating evidence suggests that there are sex differences in analgesic responses to opioid agonists. Several studies using an oral surgery pain model have reported more robust analgesia to kappa-agonist-antagonists (e.g., pentazocine, nalbuphine, butorphanol) among women than among men. However, evidence of sex differences in kappa-agonist-antagonist effects from studies of experimentally induced pain in humans is lacking. Therefore, the analgesic effects of intravenous pentazocine (0.5 mg/kg) were determined in healthy women (n = 41) and men (n = 38) using three experimental pain models: heat pain, pressure pain, and ischemic pain. Each pain procedure was conducted before and after double-blind administration of both pentazocine and saline, which occurred on separate days in counterbalanced order. Compared with saline, pentazocine produced significant analgesic responses for all pain stimuli. However, no sex differences in pentazocine analgesia emerged. Effect sizes for the sex differences were computed; the magnitude of effects was small, and an equal number of measures showed greater analgesia in men than in women. Also, analgesic responses were not highly correlated across pain modalities, suggesting that different mechanisms may underlie analgesia for disparate types of pain. These findings indicate significant analgesic responses to pentazocine in both men and women across multiple experimental pain assays, and the absence of sex differences contrasts with previous data from the oral surgery model. The most likely explanation for the discrepancy in results is that of differences in the pain assays. These findings are important because they suggest that sex differences in opioid analgesia may be specific to certain types of pain.
Author manuscript; available in PMC 2006 December 7. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript rThe melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans
  • Js Mogil
  • Wilson
  • Sg
  • Ej Chesler
  • Al Rankin
  • Kv Nemmani
  • Lariviere
  • Mk Groce
  • Mr Wallace
  • L Kaplan
  • R Staud
  • Tj Ness
  • Glover
  • M Stankova
  • A Mayorov
  • Vj Hruby
  • Je Grisel
  • Rb Fillingim
  • Liem
Mogil JS, Wilson SG, Chesler EJ, Rankin AL, Nemmani KV, Lariviere WR, Groce MK, Wallace MR, Kaplan L, Staud R, Ness TJ, Glover TL, Stankova M, Mayorov A, Hruby VJ, Grisel JE, Fillingim RB. Liem et al.Page 7 Anesthesiology. Author manuscript; available in PMC 2006 December 7. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript rThe melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. Proc Natl Acad Sci U S A 2003;100:4867–72. [PubMed: 12663858
Molecular Determinants of State-Dependent Block of Na+ Channels by Local Anesthetics
  • D Ragsdale
  • J Mcphee
  • T Scheuer
  • W Cattterall
Ragsdale D, McPhee J, Scheuer T, Cattterall W. Molecular Determinants of State-Dependent Block of Na+ Channels by Local Anesthetics. Science 1994;265:1724. [PubMed: 8085162]