ArticleLiterature Review

Neuropharmacological Properties of the Essential Oil of Bergamot for the Clinical Management of Pain-Related BPSDs

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Abstract

Background: Alzheimer's Disease (AD) accounts for approximately 50% of all cases of dementia and, in spite of the great effort for the development of disease-modifying drugs, a definitive treatment of cognitive impairment is not available yet. A perfect adherence to the current therapy of cognitive decline is needed for a better control of the disease and this is proven to reduce, though not completely abolish, the associated Behavioural and Psychological Symptoms of Dementia (BPSDs) from occurring. This cluster of symptoms, remarkably affecting patients' health-related quality of life (HRQL), is tightly associated to pain states. Antipsychotics are the only treatment for BPSDs. However, these drugs are more effective and safer in the short-term (6-12 weeks), they are able to manage aggression but not agitation and they cannot control pain. Aromatherapy with Melissa officinalis and Lavandula officinalis has been employed to handle BPSDs, but it has not provided strong evidence to offer relief from pain. 1.2. Objective: Bergamot Essential Oil (BEO) exerts antinociceptive activity through several pharmacological mechanisms: in particular, it is able to enhance autophagy, a process undergoing derangement in chronic pain. Thus, the sound pharmacological basis for clinical translation of aromatherapy with BEO in the treatment of BPSDs has been pointed out. 1.3. Conclusion: The antinociceptive effects elicited by BEO in experimental pain models make of it a possible candidate for the pharmacological management of pain-related BPSDs.

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... Therefore, low concentrations of BEO may prompt the presynaptic exocytosis of glutamate, which can act on Gq-coupled group I metabotropic glutamate autoreceptors or heteroreceptors [59]. This mechanism can induce modulation of multiple neurotransmissions dysregulated in the neuropsychiatric symptoms of dementia and initiate retrograde endocannabinoid signaling responsible for disinhibition of the descending analgesic pathway acting on GABAergic interneurons [60]. ...
... Patients affected by dementia often present alteration of the nociceptive transduction and modulation pathways, as well as age-related comorbidities responsible for chronic pain often underdetected and mistreated because of their impaired communication skills [60]. Chronic Therefore, low concentrations of BEO may prompt the presynaptic exocytosis of glutamate, which can act on Gq-coupled group I metabotropic glutamate autoreceptors or heteroreceptors [59]. ...
... Chronic Therefore, low concentrations of BEO may prompt the presynaptic exocytosis of glutamate, which can act on Gq-coupled group I metabotropic glutamate autoreceptors or heteroreceptors [59]. This mechanism can induce modulation of multiple neurotransmissions dysregulated in the neuropsychiatric symptoms of dementia and initiate retrograde endocannabinoid signaling responsible for disinhibition of the descending analgesic pathway acting on GABAergic interneurons [60]. ...
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Aging of the population makes of dementia a challenge for health systems worldwide. The cognitive disturbance is a serious but not the only issue in dementia; behavioral and psychological syndromes known as neuropsychiatric symptoms of dementia remarkably reduce the quality of life. The cluster of symptoms includes anxiety, depression, wandering, delusions, hallucinations, misidentifications, agitation and aggression. The pathophysiology of these symptoms implicates all the neurotransmitter systems, with a pivotal role for the glutamatergic neurotransmission. Imbalanced glutamatergic and GABAergic neurotransmissions, over-activation of the extrasynaptic N-methyl-D-aspartate (NMDA) receptors and alterations of the latter have been linked to the development of neuropsychiatric symptoms experienced by almost the entire demented population. Drugs with efficacy and safety for prevention or long term treatment of these disorders are not available yet. Aromatherapy provides the best evidence for positive outcomes in the control of agitation, the most resistant symptom. Demented patients often cannot verbalize pain, resulting in unrelieved symptoms and contributing to agitation. Bergamot essential oil provides extensive preclinical evidence of analgesic properties. Incidentally, the essential oil of bergamot induces anxyolitic-like effects devoid of sedation, typical of benzodiazepines, with a noteworthy advantage for demented patients. These data, together with the reported safety profile, form the rational basis for bergamot as a neurotherapeutic to be trialed for the control of behavioral and psychological symptoms of dementia.
... The improvement of life expectancy over the 21st century has led to demographic aging with a steady increase of age-related neurodegenerative pathologies [1]. Alzheimer's disease (AD) is the most widespread form of dementia estimated to affect some 75 million people by 2030 and to double by 2050 [2,3]. Chronic pain is often experienced by the elderly, ranging from 50% of community-dwelling older adults to 80% of care facilities residents, of whom 25% do not receive pain-relief [4][5][6]. ...
... It enhances morphine-induced analgesia and its dose-dependent effect is antagonized by naloxone hydrochloride and methiodide (not crossing the blood-brain barrier), suggesting the involvement of peripheral opioid mechanisms. Quite importantly, BEO is able to modulate the synaptic level of glutamate [41], involved in pain transmission and modulation through the pain descending pathway due to metabotropic glutamate receptors [3]. Its analgesic efficacy occurs also via the inhalation route [42], but it has been demonstrated not to depend on inhalation [40]. ...
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Dementia is one of the most common causes of disability worldwide characterized by memory loss, cognitive impairment, and behavioral and psychological symptoms (BPSD), including agitation. Treatment of the latter consists of the off-label use of harmful atypical antipsychotics, though a significant reduction is afforded by pain control. The use of an essential oil endowed with analgesic properties and devoid of toxicity would represent an important option for the management of agitation in dementia. Therefore, the aim of this study was to engineer a nanotechnology delivery system based on solid lipid nanoparticles loaded with bergamot essential oil (BEO) and devised in the pharmaceutical form of an odorless cream (NanoBEO) to confirm its analgesic efficacy for further development and application to control agitation in dementia. BEO has proven strong antinociceptive and anti-allodynic properties and, in its bergapten-free form, it is completely devoid of phototoxicity. NanoBEO has been studied in vivo confirming the previously reported analgesic activity of BEO to which is now added its anti-itching properties. Due to the nanotechnology delivery system, the stability of titrated BEO components is guaranteed. Finally, the latter invention, currently under patent consideration, is smell-devoid allowing efficacy and safety to be established in double-blind clinical trials; until now the latter studies have been impeded in aromatherapy by the strong odor of essential oils. A clinical trial NCT04321889 has been designed to provide information about the efficacy and safety of NanoBEO on agitation and pain in patients suffering from severe dementia.
... Sani et al. [136,137,146] studied the encapsulation of Melissa officinalis essential oil in microcapsules and bioactive films. In the first study [146], the encapsulation of essential oil in isolated whey proteins and sodium caseinate was investigated using the ultrasonication technique. ...
... Sani et al. [136,137,146] studied the encapsulation of Melissa officinalis essential oil in microcapsules and bioactive films. In the first study [146], the encapsulation of essential oil in isolated whey proteins and sodium caseinate was investigated using the ultrasonication technique. The results showed that ultrasound intensification had a negative impact, and that the smallest particle size was obtained at higher isolated whey protein levels, and with the lowest ultrasonic power. ...
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Melissa officinalis is a medicinal plant rich in biologically active compounds which is used worldwide for its therapeutic effects. Chemical studies on its composition have shown that it contains mainly flavonoids, terpenoids, phenolic acids, tannins, and essential oil. The main active constituents of Melissa officinalis are volatile compounds (geranial, neral, citronellal and geraniol), triterpenes (ursolic acid and oleanolic acid), phenolic acids (rosmarinic acid, caffeic acid and chlorogenic acid), and flavonoids (quercetin, rhamnocitrin, and luteolin). According to the biological studies, the essential oil and extracts of Melissa officinalis have active compounds that determine many pharmacological effects with potential medical uses. A new field of research has led to the development of controlled release systems with active substances from plants. Therefore, the essential oil or extract of Melissa officinalis has become a major target to be incorporated into various controlled release systems which allow a sustained delivery.
... Frequency of use of the painkillers (percentage) been proven to display the best, although not complete, control of agitation. The antinociceptive properties, demonstrated in preclinical settings, of the essential oil of bergamot (BEO) may represent a rationale for the study of its effectiveness in the management of NPSs and, mainly, agitation (Scuteri et al., 2018). BEO reduces the nociceptive response in inflammatory and neuropathic pain models and this pharmacological action may be due to its property to enhance, through its component D-limonene, basal and induced autophagy (Berliocchi et al., 2018). ...
... Derangement of this highly conserved process has been involved in neuropathic pain (Berliocchi et al., 2011), but also in the impairment of the autophagic-endocytotic-lysosomal axis, representing a risk factor for the development of AD (Parcon et al., 2018). Another interesting feature of this essential oil is that it can induce anxiolytic, though not sedative, effects (Rombolà et al., 2017) thus resulting in more suitable than benzodiazepines in demented patients (Scuteri et al., 2018). Therefore, a large clinical trial to assess the efficacy of BEO on NPSs and, in particular, agitation, is needed for an improvement of the quality of life of demented patients while waiting for the development of efficacious disease-modifying drugs. ...
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During the clinical course of dementia, beside cognitive impairment and memory loss, a very complex challenge is posed by the neuropsychiatric symptoms (NPSs). Accurate evaluation and treatment of pain impacts positively the agitation of demented patients aged ≥ 65 years. To gather information on the utilization of pain killers in demented patients a preliminary survey has been conducted in collaboration with the Calabrian Pharmacovigilance Territorial Service of the health district of Catanzaro (Italy). The study has taken into consideration the prescriptions of acetylcholinesterase inhibitors and memantine during the period ranging from July 2015 to June 2016 and the percentage of patients treated against pain with non steroidal antinflammatory drugs, opioids, and anticonvulsants have been monitored. The latter have been evaluated statistically for difference between the treatment before (pre) and after (post) the settlement of acetylcholinesterase inhibitors (AChEI) or memantine therapy. The results do support accuracy in painkillers utilization in the course of dementia in the regional population of Calabria (Italy).
... Dementia represents a public health priority, with some 55 million people affected worldwide and about 41 million of them undiagnosed [1]. Among the diverse forms of dementia, Alzheimer's disease (AD) is the most frequent standing for around two-thirds of all cases [2,3]. Despite the recent accelerated approval of aducanumab [4], without approval by the European Medicine Agency (EMA) due to contrasting efficacy results in the face of a lack of sufficient safety, disease-modifying drugs, after failures in the last years, are still not ...
... To this aim, effective and feasible pain assessment scales are unavoidable and fundamental to engineering clinical trials to establish: (1) pharmacodynamic and pharmacokinetic profiles of drugs in the fragile older population known to present physiological differences and variability in response to medications [82]; (2) information about polypharmacy [83], remarkably serious for antipsychotics and psychotropic drugs as some 49.7% of people with advanced dementia ≥ 65 years are prescribed and administered five or more medications and, in 39% of cases, at least one is a potentially inappropriate medication (PIM), based on the Beers Criteria [84], and; 3) impact of drug-to-drug [85]/herbal medicines interactions [86]. Phytocomplexes endowed with analgesic and non-benzodiazepine-like anxiolytic effects [2,[87][88][89][90][91] deserve investigation for pain [92] and, consequently, agitation [36] treatment devoid of serious adverse reactions. It is an established fact that pain in 20% of the elderly is chronic [93], treated for at least 6 months [93], and unrelieved in up to 80% of cases [94]. ...
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Up to 80% of Alzheimer’s disease (AD) patients in nursing homes experiences chronic pain and 97% develops fluctuant neuropsychiatric symptoms (NPS). Agitation, associated with unrelieved pain, is managed through antipsychotics and may increase the risk of death. Evidence is accumulating in favor of analgesia for a safer, effective therapy of agitation. The Italian version of Mobilization–Observation–Behavior–Intensity–Dementia, I-MOBID2, recently validated in the Italian setting, shows: good scale content validity index (0.89), high construct validity (Spearman rank-order correlation Rho = 0.748), reliable internal consistency (Cronbach’s α coefficient = 0.751), good-excellent inter-rater (intraclass correlation coefficient, ICC = 0.778) and test-retest (ICC = 0.902) reliability, and good inter-rater and test-retest agreement (Cohen’s K = 0.744) with 5.8 min completion time. This study intends to identify the responsiveness of the I-MOBID2 based on COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) recommendations, assessing the a priori hypotheses of (1) the efficacy of painkillers administered to severe AD patients after proper pain assessment and (2) the effect of reduction of the Cohen-Mansfield Agitation Inventory (CMAI) score and of agitation rescue medications. This protocol is approved by Calabria Region Ethics Committee protocol No. 31/2017 and follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines.
... Therefore, exploitation of the anti-migraine potential of natural compounds through reduction of trigeminal afferents facilitation is envisaged. The latter concept is even more so for those essential oils like bergamot (BEO) endowed with analgesic properties in inflammatory and neuropathic pain models [76][77][78], forming the rational basis for translational clinical studies [79,80,81], also under central sensitization and chronic administration paradigms that can recapitulate clinical conditions underlined by neurogenic inflammation. Moreover, the following clinical investigation and use of BEO is made feasible by its engineering [82] in a nanotechnology-based delivery system in the pharmaceutical form of an odorless cream for topical application, in order to be able to titrate the phytocomplex, to preserve the components from degradation and to allow double-blind clinical trials. ...
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Introduction: Migraine is the leading cause of years lived with disability in people under 50 . Electrophysiological phenomena at the basis of prodromal and headache attack phases and of chronification processes involve calcitonin-gene related peptide (CGRP) as a fundamental player become a game changer of migraine pharmacotherapy.Areas covered: The purpose of the present review is to retrace fundamental stages of CGRP from its discovery to the role in migraine pathogenesis and therapy to underscore the change of paradigm offered by the newly approved small molecules to antagonize CGRP receptor, the gepants. In particular, the development of this new class is gone over from the initial synthesis of C-terminus truncated CGRP antagonists to the development of the first generation of gepants ending with Zavegepant that can be considered the third generation.Expert opinion: The history of CGRP in migraine draws the successful road to follow for key signaling pathways of modulation of nociceptive facilitation by diencephalic and brainstem nuclei, including dopaminergic neurotransmission, orexin A and the large-conductance calcium-activated potassium (BKCa) and ATP-sensitive potassium (KATP) channels also investigating the potential of essential oils and the role of polymorphisms. Real-world post marketing long-term data are needed for gepants.
... Actually, stroke survivors do not even benefit from clinical trials on the novel preventative treatment of migraine, e.g., the anticalcitonin generelated peptide monoclonal antibody eptinezumab that can provide rapid and longer-lasting action (12). This is often due to the lack of use of pain scales for an objective pain assessment validated in specific populations, e.g., patients affected by stroke, and this problem becomes even more worrying for patients with aphasia and noncommunicative and in the pandemic emergency (13)(14)(15)(16). Robot-assisted neurorehabilitation for patients with stroke having the Integrated Robotic System for Stroke (IRSS) prototype Automatic Recovery Arm Motility Integrated System (ARAMIS) has provided a significant improvement of motor recovery (17). ...
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Background Stroke is one of the most frequent causes of death and disability worldwide. It is accompanied by the impaired motor function of the upper extremities in over 69% of patients up to hemiplegia in the following 5 years in 56% of cases. This condition often is characterized by chronic poststroke pain, difficult to manage, further worsening quality of life. Poststroke pain occurs within 3–6 months. Robot-assisted neurorehabilitation using the Automatic Recovery Arm Motility Integrated System (ARAMIS) has proven efficacy in motor function recovery exploiting the movements and the strength of the unaffected arm. The rationale of the ROBOCOP (ROBOtic Care of Poststroke pain) randomized trial is the assessment of the impact of robot-assisted functional and motor recovery on the prevention of poststroke pain. Methods A total of 118 patients with hemiplegic arms due to stroke will be enrolled and randomly allocated with a 1:1 ratio to ARAMIS or conventional neurorehabilitation group. After a baseline screening at hospital discharge, ARAMIS or conventional rehabilitation will be performed for 8 weeks. The primary endpoint is the prevention of the development of poststroke pain and the secondary endpoints are prevention of spasticity and efficacy in clinical motor rehabilitation. The primary outcome measures consist in the visual analog scale and the doleur neuropatique 4 and the secondary outcome measures include: the Modified Ashworth Scale, the Resistance to Passive movement Scale; the Upper Extremity Subscale of the Fugl–Meyer Motor Assessment; the Action Research Arm Test; the Barthel Index for activities of daily living; and the magnetic resonance imaging (MRI) recovery-related parameters. After baseline, both primary and secondary outcome measures will be performed in the following time points: 1 month after stroke ( t 1 , half of the rehabilitation); 2 months after stroke ( t 2 , after rehabilitation); and 3 months ( t 3 ) and 6 months ( t 4 ) after stroke, critical for poststroke pain development. Discussion This is the first clinical trial investigating the efficacy of robot-assisted neurorehabilitation using ARAMIS on poststroke pain prevention. This study could remarkably improve the quality of life of stroke survivors.
... The evidence that patients suffering from dementia develop an aberrant transmission and modulation of pain [42], together with age-related comorbidities associated with pain, accounts for the presence of chronic pain states in 50% demented people [43], reaching 80% in long-term care facilities [44], often under-detected [45,46]. Pain assessment is difficult in patients suffering from severe dementia due to their reduced communication skills. ...
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The coronavirus disease 2019 (COVID-19) pandemic imposes an unprecedented lifestyle, dominated by social isolation. In this frame, the population to pay the highest price is represented by demented patients. This group faces the highest risk of mortality, in case of severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection, and they experience rapid cognitive deterioration, due to lockdown measures that prevent their disease monitoring. This complex landscape mirrors an enhancement of neuropsychiatric symptoms (NPSs), with agitation, delirium and reduced motor performances, particularly in non-communicative patients. Due to the consistent link between agitation and pain in these patients, the use of antipsychotics, increasing the risk of death during COVID-19, can be avoided or reduced through an adequate pain treatment. The most suitable pain assessment scale, also feasible for e-health implementation, is the Mobilization-Observation-Behaviour-Intensity-Dementia (MOBID-2) pain scale, currently under validation in the Italian real-world context. Here, we report the case of an 85-year-old woman suffering from mild cognitive impairment, subjected to off-label treatment with atypical antipsychotics, in the context of undertreated pain, who died during the pandemic from an extensive brain hemorrhage. This underscores the need for appropriate assessment and treatment of pain in demented patients.
... The latter observation supports evidence of having BEO anxiolytic-like effects, and that limonene plays an important role since high locomotory activity is associated with attempts to escape, resulting in being a remarkable behavioral indicator of anxiety [18]. Incidentally, these effects have been demonstrated to be devoid of the sedation that is typical of benzodiazepines [19] and to involve serotonergic neurotransmission [20] that is separate from the possible role of the glutamatergic and endocannabinoid systems [21][22][23]. This is fundamental since the glutamatergic [24,25] and serotonergic [26] mechanisms are significantly involved in aging and neurodegeneration and, thus, they are also involved in the mechanism of action of rapid acting antidepressants [27]. ...
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Bergamot essential oil (BEO) is endowed with consistent and reproducible antinociceptive and anti-allodynic properties when administered via an inhalation route. However, the effects of its main constituents and of its decolored (DEC) and deterpenated (DET) fractions, which are enriched in limonene or in linalool and linalyl acetate, respectively, on spontaneous motor activity related to anxiety and on formalin-induced licking/biting biphasic behavior have never been investigated before. Therefore, the present research aims to characterize the role of BEO components on an experimental pain model that is relevant to clinical translation. Under our present experimental conditions, a paper filter disc soaked with different volumes of the phytocomplex and of its fractions that was applied at the edge of the observation chamber allowed the effects on the spontaneous motor activity and on the formalin-induced nocifensive response in ddY-strain mice to be studied. The present research demonstrated the effects of the DEC fraction of BEO on motor activity and on formalin-induced licking/biting behavior for the first time, proving that limonene is implicated in reduced motor activity and that it is important for the analgesic effect.
... Medicinal plant extracts, useful for different therapeutic purposes, e.g., aromatherapy in dementia [165][166][167][168], may influence the pharmacokinetics of co-administered drugs then inducing modifications in plasma drug levels. Consequently, it may not reach a therapeutic response or, alternatively, it may cause drug-induced toxicity. ...
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The therapeutic efficacy of a drug or its unexpected unwanted side effects may depend on the concurrent use of a medicinal plant. In particular, constituents in the medicinal plant extracts may influence drug bioavailability, metabolism and half-life, leading to drug toxicity or failure to obtain a therapeutic response. This narrative review focuses on clinical studies improving knowledge on the ability of selected herbal medicines to influence the pharmacokinetics of co-administered drugs. Moreover, in vitro studies are useful to anticipate potential herbal medicine-drug interactions. In particular, they help to elucidate the cellular target (metabolic or transporter protein) and the mechanism (induction or inhibition) by which a single constituent of the herbal medicine acts. The authors highlight the difficulties in predicting herbal–drug interactions from in vitro data where high concentrations of extracts or their constituents are used and pharmacokinetics are missed. Moreover, the difficulty to compare results from human studies where different kinds of herbal extracts are used is discussed. The herbal medicines discussed are among the best sellers and they are reported in the “Herbal Medicines for Human Use” section of the European Medicinal Agency (EMA).
... Aromatherapy is part of phytotherapy and is based on the use of pure essential oils from fragrant plants to relieve health problems and improve QoL. The potential effects of essential oils are varied, including promotion of relaxation and sleep, relief of pain (179), reduction of depressive symptoms. Aromatherapy might be a useful intervention for people with cognitive disturbances, who are confused, or for whom verbal interaction is difficult and current conventional medicine provides only partial benefit (180). ...
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Background: Alzheimer's disease (AD) and dementia are chronic diseases with progressive deterioration of cognition, function, and behavior leading to severe disability and death. The prevalence of AD and dementia is constantly increasing because of the progressive aging of the population. These conditions represent a considerable challenge to patients, their family and caregivers, and the health system, because of the considerable need for resources allocation. There is no disease modifying intervention for AD and dementia, and the symptomatic pharmacological treatments has limited efficacy and considerable side effects. Non-pharmacological treatment (NPT), which includes a wide range of approaches and techniques, may play a role in the treatment of AD and dementia. Aim: To review, with a narrative approach, current evidence on main NPTs for AD and dementia. Methods: PubMed and the Cochrane database of systematic reviews were searched for studies written in English and published from 2000 to 2018. The bibliography of the main articles was checked to detect other relevant papers. Results: The role of NPT has been largely explored in AD and dementia. The main NPT types, which were reviewed here, include exercise and motor rehabilitation, cognitive rehabilitation, NPT for behavioral and psychological symptoms of dementia, occupational therapy, psychological therapy, complementary and alternative medicine, and new technologies, including information and communication technologies, assistive technology and domotics, virtual reality, gaming, and telemedicine. We also summarized the role of NPT to address caregivers' burden. Conclusions: Although NPT is often applied in the multidisciplinary approach to AD and dementia, supporting evidence for their use is still preliminary. Some studies showed statistically significant effect of NPT on some outcomes, but their clinical significance is uncertain. Well-designed randomized controlled trials with innovative designs are needed to explore the efficacy of NPT in AD and dementia. Further studies are required to offer robust neurobiological grounds for the effect of NPT, and to examine its cost-efficacy profile in patients with dementia.
... In particular, the effectiveness of the analgesics administered to patients affected by severe dementia and the reduction of agitation due to analgesic treatment will be assessed. The I-MOBID2 is the pain assessment tool selected for the evaluation of pain in a randomized, double-blind, placebo-controlled trial (NCT04321889) [48] to evaluate the efficacy of NanoBEO [49], the engineered essential oil of bergamot endowed with strong preclinically proven analgesic [44,50] and anxiolytic [51] properties, in the control of agitation and pain in patients suffering from severe dementia. ...
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The 97% of dementia patients develops fluctuant neuropsychiatric symptoms often related to under-diagnosed and unrelieved pain. Up to 80% severe demented nursing home residents experiences chronic pain due to age-related comorbidities. Patients lacking self-report skills risk not to be appropriately treated for pain. Mobilization-Observation-Behavior-Intensity-Dementia (MOBID2) is the sole pain scale to consider the frequent co-occurrence of musculoskeletal and visceral pain and to unravel concealed pain through active guided movements. Accordingly, the Italian real-world setting can benefit from its translation and validation. This clinical study provides a translated, adapted and validated version of the MOBID2, the Italian I-MOBID2. The translation, adaptation and validation of the scale for non-verbal, severe demented patients was conducted according to current guidelines in a cohort of 11 patients over 65 with mini-mental state examination ≤ 12. The I-MOBID2 proves: good face and scale content validity index (0.89); reliable internal consistency (Cronbach's α = 0.751); good to excellent inter-rater (Intraclass correlation coefficient, and test-retest (ICC = 0.902) reliability. The construct validity is high (Rho = 0.748 p < 0.05 for 11 patients, Spearman rank order correlation of the overall pain intensity score with the maximum item score of I-MOBID2 Part 1; rho=0.895 p < 0.01 for 11 patients , for the overall pain intensity score with the maximum item score of I-MOBID2 Part 2) and a good rate of inter-rater and test-retest agreement was demonstrated by Cohen's K = 0.744. The average execution time is of 5.8 min, thus making I-MOBID2 a useful tool suitable also for future development in community setting with administration by caregivers.
... In the last decade, preclinical studies have supported the therapeutic use of BEO. Particularly, bergamot oil is endowed with remarkable neurobiological effects [8,9] partially deriving from an interference with basic mechanisms finely tuning synaptic plasticity under physiological [10,11] and pathological conditions, i.e., brain ischemia [12], pain [13][14][15][16][17][18], and behavioural and psychological symptoms of dementia [19,20]. Under basal condition, BEO elevates extracellular levels of discrete amino acids with neurotransmitter function after systemic or focal administration in the hippocampus of freely moving rats [10]. ...
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Anxiety disorders are one of the most common mental disorders, and benzodiazepines (BDZs), acting on gamma-aminobutyric acid type A (GABA-A) receptor complex, represent the most common antianxiety medications in the world. However, chronic BDZ use elicits several adverse reactions. Reportedly, aromatherapy is safer for the management of anxiety. Bergamot essential oil (BEO) extracted from Citrus bergamia Risso et Poiteau fruit, like other essential oils, is widely used in aromatherapy to relieve symptoms of stress-induced anxiety. Interestingly, preclinical data indicate that BEO induces anxiolytic-like/relaxant effects in animal behavioural tasks not superimposable to those of benzodiazepine diazepam. To better elucidate the involvement of GABAergic transmission, the present study examines the effects of pretreatment with flumazenil (FLZ), a benzodiazepine site antagonist, on BEO effects using open-field task (OFT) in rats. The data yielded show that FLZ does not significantly affect behavioural effects of the phytocomplex. These results demonstrate the lack of overlapping between BEO and BDZ behavioural effects, contributing to the characterization of the neurobiological profile of the essential oil for its rational use in aromatherapy.
... Actually, the clinical successes of the application of many psychotropic drugs are characterized by non-response to treatment, non-adherence to prolonged treatment, and several side effects [7]. Approaches to natural products have been deeply studied [8][9][10][11], which could provide therapeutic options. Keeping in mind that mood disorders involve complex neural dysregulation, a clinically safe agent with several neural mechanisms could offer a better treatment. ...
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The essential oil obtained by the fresh fruit of Citrus bergamia Risso et Poiteau is used worldwide in aromatherapy to reduce pain, facilitate sleep induction, and/or minimize the effects of stress-induced anxiety. Preclinical pharmacological data demonstrate that bergamot essential oil (BEO) modulates specific neurotransmissions and shows an anxiolytic-relaxant effect not superimposable to that of the benzodiazepine diazepam, suggesting that neurotransmissions, other than GABAergic, could be involved. Several studies on essential oils indicate a role for serotonergic (5-HT) neurotransmission in anxiety. Interestingly, among serotonergic receptors, the 5-HT1A subtype seems to play a key role in the control of anxiety. Here, we report that modulation of the 5-HT1A receptor by selective agonist ((±)8-OH-DPAT) or antagonist (WAY-100635) may influence some of the anxiolytic-relaxant effects of BEO in Open Field and Elevated Plus Maze tests.
... EOs have shown several beneficial properties, many of which concern the treatment of neurologic diseases, mood disturbances, and pain. Modulation of the γ-aminobutyric acid (GABA) neurotransmission and blockade of neuronal voltage-gated sodium channels (Na + channels) as well as activity on serotonergic neurotransmission are proposed as mechanisms involved in the action of EOs endowed with anxiolytic and anti-nociceptive properties like bergamot essential oil (BEO) Scuteri et al., 2018a;Scuteri et al., 2019a;Scuteri et al., 2019b;Rombolà et al., 2019;Rombola et al., 2020), lavender essential oil (LEO) (Lopez et al., 2017), and melissa (lemon balm) (Abuhamdah et al., 2008;Awad et al., 2009). The cholinergic system is targeted by extracts of plants as sage (Perry et al., 2000;Savelev et al., 2003;Savelev et al., 2004), ginkgo (Stein et al., 2015;Zhang et al., 2018), and lemon balm (Dastmalchi et al., 2009;Guginski et al., 2009), showing therapeutic potential for diseases like dementia. ...
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Background: The demand for essential oils (EOs) has been steadily growing over the years. This is mirrored by a substantial increase in research concerned with EOs also in the field of inflammatory and neuropathic pain. The purpose of this present systematic review and meta-analysis is to investigate the preclinical evidence in favor of the working hypothesis of the analgesic properties of EOs, elucidating whether there is a consistent rational basis for translation into clinical settings. Methods: A literature search has been conducted on databases relevant for medical scientific literature, i.e., PubMed/MEDLINE, Scopus, and Web of Science from database inception until November 2, 2020, following the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) criteria for systematic reviews and meta-analyses. Results: The search was conducted in order to answer the following PICOS (participants/population, interventions, comparisons, outcomes, and study design) question: are EOs efficacious in reducing acute nociceptive pain and/or neuropathic pain in mice experimental models? The search retrieved 2,491 records, leaving 954 studies to screen after the removal of duplicates. The title and abstract of all 954 studies were screened, which left 127 records to evaluate in full text. Of these, 30 articles were eligible for inclusion. Conclusion: Most studies (27) assessed the analgesic properties of EOs on acute nociceptive pain models, e.g. the acetic acid writhings test, the formalin test, and the hot plate test. Unfortunately, efficacy in neuropathic pain models, which are a more suitable model for human conditions of chronic pain, had fewer results (only three studies). Moreover, some methodologies raised concerns in terms of the risk of bias. Therefore, EOs with proven efficacy in both types of pain were corroborated by methodologically consistent studies, like the EO of bergamot, which should be studied in clinical trials to enhance the translational impact of preclinical modeling on clinical pain research.
... derivatives, BEO was described to possess melanogenic, antinociceptive, antiproliferative, sedative, anxiolytic, neuroprotective, antioxidant, and antimicrobial activities [63]. Neuropharmacological studies of BEO showed its usefulness in neuroprotection (even in the course of experimental brain ischemia), chronic pain control, and in the management of stress, anxiety and anxiety-related conditions [53,[64][65][66][67]. It has been suggested that the pharmacological mechanism of action of BEO on the central nervous system can involve different neuronal pathways, with an integrated effect on both 5-HT and GABA-A receptors and with an anxiety-lowering activity which is not superimposable to that of benzodiazepines [68]. ...
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Bergamot essential oil (BEO) is the result of the mechanical manipulation (cold pressing) of the exocarp (flavedo) of the hesperidium of Citruslimon (L.) Osbeck Bergamot Group (synonym Citrus × bergamia Risso & Poit.), resulting in the bursting of the oil cavities embedded in the flavedo and the release of their contents. It is chemically dominated by monoterpene hydrocarbons (i.e., limonene), but with significant percentages of oxygenated monoterpenes (i.e., linalyl acetate) and of non-volatile oxygen heterocyclic compounds (i.e., bergapten).
... Indeed, all the included studies were quite old and dating prior to the 2009 CPSP redefinition (Klit et al., 2009), which made the differential diagnosis between CPSP and other types of post-stroke pain clearer and more reliable. Pain assessment represents an important issue in non-communicative patients, who can have difficulties to describe their pain, contributing to behavioral disturbances in some neurological conditions Scuteri et al., 2018;Scuteri et al., 2019a;Scuteri et al., 2019b). Indeed, in the real-life clinical setting, the use of opioids in patients with post-stroke pain, who are not able to communicate is frequent, but the response to treatment is unclear (Schuster et al., 2020). ...
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Background: Post-stroke pain is one of the most common sequelae of stroke, which stands among the leading causes of death and adult-acquired disability worldwide. The role and clinical efficacy of opioids in post-stroke pain syndromes is still debated. Objectives: Due to the important gap in knowledge on the management of post-stroke pain, this systematic review aimed at assessing the efficacy of opioids in post-stroke pain syndromes. Methods: A literature search was conducted on databases relevant for medical scientific literature, i.e. PubMed/MEDLINE, Scopus, Web of Science and Cochrane Library databases from databases inception until August 31 st , 2020 for clinical trials assessing the effects of opioids and opioid antagonists on pain reduction and pain related symptoms in patients with post-stroke pain syndromes. Studies assessing the effects of other medications (e.g., tricyclic antidepressant, pregabalin) or non - pharmacological management strategies (e.g., neurostimulation techniques) were excluded. The selected studies have been subjected to examination of the risk of bias. Results: The literature search retrieved 83,435 results. After duplicates removal, 34,285 articles were title and abstract screened. 25 full texts were assessed and 8 articles were identified to be eligible for inclusion in the qualitative summary and narrative analysis, of which three were placebo-controlled and two were dose-response. Among placebo-controlled studies, two evaluated the analgesic effect of morphine and one assessed the effects of the opioid antagonist naloxone on patients with central post-stroke pain. With regard to dose-response studies, both were on patients with central post-stroke pain, one assessing the efficacy of levorphanol, and the other on naloxone. Seven out of eight included studies showed an overall slight analgesic effect of opioids, with less consistent effects on other pain-related symptoms (e.g., mood, quality of life). The randomized controlled trials were subjected to meta-analysis and rating of the quality of evidence for the two outcomes considered according to GRADE (Grading of Recommendations, Assessment, Development and Evaluations) system. The overall results are inconclusive because of the small number of studies and of patients. Conclusions: The limited number of the included studies and their heterogeneity in terms of study design do not support the efficacy of opioids in post-stroke pain and in pain-related outcomes. Large double-blind randomized clinical trials with objective assessment of pain and related symptoms are needed to further investigate this topic.
... Fifty million people suffer from dementia worldwide, and the most common form is represented by Alzheimer's disease (AD) [1]. The lack of a definite etiopathogenesis makes the discovery of disease-modifying drugs difficult (see [2,3]). Several factors contribute to delayed diagnosis of dementia [4,5], and this means the two-thirds of all cases go missed in primary care [6,7]. ...
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Purpose: Data concerning the number of diagnoses and of the drugs prescribed to patients affected by dementia are still scarce. Here we test whether or not (1) prescription of symptomatic drugs against Alzheimer's disease (AD) may approximate the number of patients affected by dementia in Italy and (2) adherence to this treatment affects the pattern of prescription of drugs (i.e. antipsychotics and antidepressants) for behavioural and psychological symptoms of dementia (BPSD) and the previously reported limited prescription of analgesics. Methods: This retrospective observational study concerns 84,235 subjects older than 60 years and registered in the provincial prescription database of the health district of Cosenza accounting for a population of 298,000 inhabitants. The prescribing pattern of antipsychotics, antidepressants, and analgesics has been investigated in patients receiving concurrent prescriptions of acetylcholinesterase inhibitors (AChEI) and/or memantine. Data from a single centre for cognitive disturbances and dementia (CDCD) in the same health district were used to explore at which stage dementia was diagnosed. The study was approved by Calabria Region Ethical Committee no. 31/2017 and registered on October 31, 2017. Results: The data show that 859 patients are treated with AChEI and/or memantine; 420 patients (48.89%) receive at least 80% of the recommended medications. CDCD data indicate a delay in dementia diagnosis, which often was made when the patients were moderately to severely demented (Mini Mental State Examination, MMSE ≤ 20). Adherence did not influence prescription of most of the drugs explored, but use of non-steroidal anti-inflammatory drugs was higher in non-adherent patients. Antipsychotics and antidepressants are frequently used (20.61-20.71% and 42.37-51.43%, respectively), and this, at least in part, might stem from the observed under-treatment of chronic pain (opioids are prescribed in the 4.76% and 12.46% of adherent and non-adherent patients and gabapentin and pregabalin are used in the 4.29% and 4.07% of adherent and non-adherent patients respectively), resulting in more frequent BPSD. 16.43% of patients receive antipsychotics for longer than 6-12 weeks. Conclusion: This 2-year period study, including a wide cohort of community demented patients, shows that dementia is diagnosed late and that prevalence of BPSD prescriptions is high and not impacted by adherence to anti-dementia drugs. The rate of prescription of potentially harmful antipsychotics and antidepressants appears to be high though whether the concomitantly observed limited prescription of analgesics might be a contributing factor needs to be further investigated. Our data support the development of strategies to improve the management of BPSD.
... In particular, 50 million people worldwide suffer from dementia and this number will likely triple by 2050 (Patterson, 2018). The most affected segment of population is represented by adults older than 65 years, often presenting comorbidities responsible for pain states, (see (Scuteri et al., 2018b)) e.g. arthritis, herpes zoster, diabetes accompanied by neuropathy and retinopathy (see (Scuteri et al., 2019b)) and migraine, disabling (see (Scuteri et al., 2019a)), and difficult to treat (see (Scuteri et al., 2020)). ...
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Improved living conditions have induced an increase of lifespan often accompanied by comorbidities, responsible for pain, and by cognitive impairment and dementia, impairing communication capabilities. In most cases, the elderly do not receive pain relief because of underdiagnosis and of aging-induced changes of systems affecting nociceptive response. Unrelieved pain is involved in the development of behavioral symptoms, as agitation, representing a difficult challenge in this fragile population. Aged C57BL/6 mice and amyloid precursor protein (APP) mice display behavioral disturbances that mimic behavioral and psychological symptoms of dementia (BPSD). Therefore, this original study focuses on the influence of aging on nociception to provide insight into the occurrence of BPSD. We have investigated how aging can affect nociception after formalin administration and gabapentin effect in C57BL/6 mice, since it represents one of the treatments of choice for chronic neuropathic pain. Based on our results, changes of nociceptive behavior in response to an algogen stimulus occur during aging. Formalin-induced behavioral pattern in older C57BL/6 mice presents a temporal shift and an increase in the peak amplitudes. Our data show that the effectiveness of gabapentin is influenced by the age of the animal; though preliminary, the latter provide evidence upon which formalin test induced long-lasting mechanical allodynia might be a reliable as rapid and viable persistent pain model. The disclosed differences in effectiveness of gabapentin according to age can form the rational basis to deepen the study of pain treatment in the elderly.
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Up to 80 % nursing home residents with dementia experiences chronic pain. Contextually, 97 % presents fluctuant neuropsychiatric symptoms (NPS). Among the most challenging is agitation, connected with undertreated pain and managed through neuroleptics doubling death risk. Evidence is accumulating in favor of the involvement of the endocannabinoid system in nociception and NPS. This double-blind, placebo-controlled, randomized trial (NAbiximols Clinical Translation To the treatment of Pain and Agitation In Severe Dementia [NACTOPAISD]) aims at investigating efficacy and safety of oral spray nabiximols, containing Δ9-tetrahydrocannabinol and cannabidiol (Sativex®), for pain and agitation treatment in severe dementia patients (Mini-Mental State Examination ≤ 12) over 65. The coprimary endpoints are efficacy on pain and agitation, assessed through the recently validated Italian Mobilization–Observation–Behavior–Intensity–Dementia and the Cohen-Mansfield Agitation Inventory. The secondary endpoint is the evaluation of efficacy duration after wash-out and the assessment of quality of life through the DEMQOL. Any adverse events will be reported. The results undergo statistical analysis plan. NACTOPAISD might provide rationale for a translational safer pain and agitation treatment in severe dementia. It is approved by Calabria Region Ethics Committee and follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) and the Consolidated Standards of Reporting Trials (CONSORT) statements.
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Murine models are fundamental in the study of clinical conditions and the development of new drugs and treatments. Transgenic technology has started to offer advantages in oncology, encompassing all research fields related to the study of painful syndromes. Knockout mice or mice overexpressing genes encoding for proteins linked to pain development and maintenance can be produced and pain models can be applied to transgenic mice to model the most disabling neurological conditions. Due to the association of movement disorders with sensitivity and pain processing, our group focused for the first time on the role of the torsinA gene GAG deletion—responsible for DYT1 dystonia—in baseline sensitivity and neuropathic responses. The aim of the present report are to review the complex network that exists between the chaperonine-like protein torsinA and the baseline sensitivity pattern—which are fundamental in neuropathic pain—and to point at its possible role in neurodegenerative diseases.
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Pain is underdiagnosed and often not adequately treated, contributing to behavioral and psychological symptoms of dementia (BPSD). BPSD are treated with atypical antipsychotics that are associated with severe cerebrocardiovascular effects. Interestingly, treatment of pain may reduce agitation. Research is focusing on nonpharmacological treatment, such as aromatherapy, for pain and BPSD in dementia. This clinical study will assess the effect on agitation in severely demented elderly of BEO loaded in a nanotechnological odorless cream indistinguishable from placebo. This is a protocol for a randomized, double‐blind, placebo‐controlled trial (NCT04321889). A total of 134 patients aged ≥65 years with severe dementia (mini‐mental state examination <12) will be recruited and randomly allocated 1:1 to either BEO or placebo group. After baseline screening, BEO (80 mg) cream or placebo cream will be trans‐dermally applied on both arms twice a day for 4 weeks with a 4‐week follow‐up period. The effect on agitation will be the primary endpoint. Any adverse events will be reported. A double‐blind, clinical trial evaluating efficacy and safety of an essential oil endowed with strong analgesic properties has never been carried out before. This study could form the basis for a safer and more effective treatment of BPSD in severe dementia.
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Neuropathic pain is characterized by mechanical allodynia and thermal hyperalgesia to heat, and it affects some 20% of European population. Patients suffering from several neurologic diseases experience neuropathic pain, often finding no relief in therapy. Transgenic mice expressing the gene encoding the human mutant (hMT) or the human wild-type (hWT) torsin A represent a preclinical model of DYT1 dystonia which is the most common form of early-onset inherited dystonia. Baseline thermal sensitivity and hyperalgesia to heat have never been studied in models of dystonia. Therefore, the aim of this research has been to characterize thermal sensitivity in baseline conditions and hyperalgesia to heat after the induction of neuropathic pain through the spinal nerve ligation (SNL) model in mice overexpressing human wild-type and mutated torsin A in comparison to non-transgenic C57BL/6 mice. According to our results, the paw withdrawal latency time to heat in the Hargreaves’ test is significantly lower in the hMT mice (Kruskal–Wallis test = 6.933; p = 0.0312*; hMT vs. hWT p = 0.0317*). On the other hand, no significant differences in SNL-induced thermal hyperalgesia was found among the three strains (Friedman test = 4.933; p = 0.1019). Future studies are needed to better understand the role of torsin A in sensory processing of heat stimuli.
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Background Purpose of the present systematic review is to investigate preclinical evidence in favor of the working hypothesis of efficacy of cannabinoids in ocular pain treatment. Methods Literature search includes the most relevant repositories for medical scientific literature from inception until November, 24 2021. Data collection and selection of retrieved records adhere to PRISMA criteria. Results In agreement with a priori established protocol the search retrieved 2471 records leaving 479 results after duplicates removal. Eleven records result from title and abstract screening to meet the inclusion criteria; only 4 results are eligible for inclusion in the qualitative synthesis impeding meta-analysis. The qualitative analysis highlights the antinociceptive and anti-inflammatory efficacy of Δ8-tetrahydrocannabinol, cannabidiol and its derivative HU-308 and of new racemic CB1 allosteric ligand GAT211 and its enantiomers GAT228 and GAT229. Moreover, CB2R agonists RO6871304 and RO6871085 and CB2R ligand HU910 provide evidence of anti-inflammatory efficacy. CB2 agonist HU308 reduces of 241% uveitis-induced leukocyte adhesion and changes lipidome profile. Methodological and design issues raise concern of risk of bias and the amount of studies is too small for generalization. Furthermore, the ocular pain model used can resemble only inflammatory but not neuropathic pain. Conclusions The role of the endocannabinoid system in ocular pain is underinvestigated, since only two studies assessing the effects of cannabinoid receptors modulators on pain behavior and other two on pain-related inflammatory processes are found. Preclinical studies investigating the efficacy of cannabinoids in ocular inflammatory and neuropathic pain models are needed to pave the way for clinical translation.
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During the past 25 years, international meetings organized every second year by the pharmacologists of the University of Calabria have represented an awaited appointment largely participated by young scientists to discuss basic and clinical research concerned with hot topics in biomedicine. This year, high caliber international scientists met on May 4th-5th, 2017 with young researchers at the Club of the University of Calabria (Cosenza, Italy) in order to make the point on neurodegenerative diseases, affecting mainly the aging brain and also to share emerging strategies for a better therapeutic management of these diseases. Participants from USA, Germany, Russia, Japan, England, Serbia and Italy created a friendly atmosphere that allowed a lively and open discussion making the meeting a success. The beauty of the Norman-Swabian Castle of Byzantine origin (a.d. 937) of Cosenza, the Civic Museum of the Byzantine Icons and Traditions of Frascineto (CS) and the hospitality of Altomonte (CS) made the rest.
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Preclinical studies have recently highlighted that bergamot essential oil (BEO) is endowed with remarkable neurobiolological effects. BEO can affect synaptic transmission, modulate electroencephalographic activity and it showed neuroprotective and analgesic properties. The phytocomplex, along with other essential oils, is also widely used in aromatherapy to minimize symptoms of stress-induced anxiety and mild mood disorders. However, only limited preclinical evidences are actually available. This study examined the anxiolytic/sedative-like effects of BEO using an open field task (OFT), an elevated plus-maze task (EPM), and a forced swimming task (FST) in rats. This study further compared behavioural effects of BEO to those of the benzodiazepine diazepam. Analysis of data suggests that BEO induces anxiolytic-like/relaxant effects in animal behavioural tasks not superimposable to those of the DZP. The present observations provide further insight to the pharmacological profile of BEO and support its rational use in aromatherapy.
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The treatment of agitation and aggression, typical Behavioural and Psychological Symptoms of Dementia (BPSDs) of Alzheimer’s Disease (AD), is one of the most complicated aspects of handling patients suffering from dementia. Currently, the management of these symptoms often associated with an increased pain perception, which notably reduces the patients’ quality of life (QoL), relies on the employment of antipsychotic drugs. Unfortunately, the use of these pharmacological agents has some limits: in the long term, they do not result in being equally effective as in the first weeks of treatment and they present important side effects. Therefore, there is growing interest, supported by clinical evidence, in aromatherapy for the control of agitation, aggression, and psychotic symptoms. Some molecular mechanisms have been proposed to explain the behavioural effects of essential oils, as the whole phytocomplex or the single components, but important basic research effort is still needed. For this reason, rigorous preclinical studies are necessary in order to understand the pharmacological basis of aromatherapy in the treatment of BPSDs and to widen the cluster of effective essential oils in pharmacotherapeutic practice.
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Group I metabotropic glutamate (mGlu) receptors consists of mGlu1 and mGlu5 receptor subtypes. These receptors are widely distributed in the central nervous system (CNS), where they preferentially mediate facilitatory signaling in neurones and glial cells, mainly by favoring phospholipase (PLC) translocation. Based on the literature so far available, group I Metabotropic glutamate receptors (mGluRs) are preferentially expressed at the postsynaptic side of chemical synapsis, where they participate in the progression of the chemical stimulus. Studies, however, have shown the presence of these receptors also at the presynaptic level, where they exert several functions, including the modulation of transmitter exocytosis. Presynaptic Group I mGluRs can be both autoreceptors regulating release of glutamate and heteroreceptors regulating the release of various transmitters, including GABA, dopamine, noradrenaline, and acetylcholine. While the existence of presynaptic release-regulating mGlu5 receptors is largely recognized, the possibility that mGlu1 receptors also are present at this level has been a matter of discussion for a long time. A large body of evidence published in the last decade, however, supports this notion. This review aims at revisiting the data from in vitro studies concerning the existence and the role of release-regulating mGlu1 receptors presynaptically located in nerve terminals isolated from selected regions of the CNS. The functional interaction linking mGlu5 and mGlu1 receptor subtypes at nerve terminals and their relative contributions as modulators of central transmission will also be discussed. We apologize in advance for omission in our coverage of the existing literature.
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Pain is underdetected and undertreated in people with dementia. We aimed to investigate the prevalence of pain in people with dementia admitted to general hospitals and explore the association between pain and behavioural and psychiatric symptoms of dementia (BPSD). We conducted a longitudinal cohort study of 230 people, aged above 70, with dementia and unplanned medical admissions to 2 UK hospitals. Participants were assessed at baseline and every 4 days for self-reported pain (yes/no question and FACES scale) and observed pain (Pain Assessment in Advanced Dementia scale [PAINAD]) at movement and at rest, for agitation (Cohen-Mansfield Agitating Inventory [CMAI]) and BPSD (Behavioural Pathology in Alzheimer Disease Scale [BEHAVE-AD]). On admission, 27% of participants self-reported pain rising to 39% on at least 1 occasion during admission. Half of them were able to complete the FACES scale, this proportion decreasing with more severe dementia. Using the PAINAD, 19% had pain at rest and 57% had pain on movement on at least 1 occasion (in 16%, this was persistent throughout the admission). In controlled analyses, pain was not associated with CMAI scores but was strongly associated with total BEHAVE-AD scores, both when pain was assessed on movement (β = 0.20, 95% confidence interval [CI] = 0.07-0.32, P = 0.002) and at rest (β = 0.41, 95% CI = 0.14-0.69, P = 0.003). The association was the strongest for aggression and anxiety. Pain was common in people with dementia admitted to the acute hospital and associated with BPSD. Improved pain management may reduce distressing behaviours and improve the quality of hospital care for people with dementia.
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This study investigated the effect of bergamot essential oil (BEO) or linalool, a major volatile component of BEO, on the nociceptive response to formalin. Plantar subcutaneous injection of BEO or linalool into the ipsilateral hindpaw reduced both the first and late phases of the formalininduced licking and biting responses in mice. Plantar subcutaneous injection of BEO or linalool into the contralateral hindpaw did not yield an antinociceptive effect, suggesting that the antinociceptive effect of BEO or linalool in the formalin test occurred peripherally. Intraperitoneal and plantar subcutaneous injection pretreatment with naloxone hydrochloride, an opioid receptor antagonist, significantly attenuated both BEO- and linalool-induced antinociception. Pretreatment with naloxone methiodide, a peripherally acting opioid receptor antagonists, also significantly antagonized the antinociceptive effects of BEO and linalool. Our results provide evidence for the involvement of peripheral opioids in antinociception induced by BEO and linalool. These results suggest that activation of peripheral opioid receptors may play an important role in reducing formalin-induced nociception.
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: Autophagy is a homeostatic degradative process essential for basal turnover of long-lived proteins and organelles as well as for removal of dysfunctional cellular components. Dysregulation of the autophagic machinery has been recently associated to several conditions including neurodegenerative diseases and cancer, but only very few studies have investigated its role in pain processing. We previously described autophagy impairment at the spinal cord in the experimental model of neuropathic pain induced by spinal nerve ligation (SNL). In this study, we characterized the main autophagic markers in two other common experimental models of neuropathic pain, the chronic constriction injury (CCI) and the spared nerve injury (SNI). The different modulation of LC3-I, Beclin 1 and p62 suggested that autophagy is differentially affected in the spinal dorsal horn depending on the type of peripheral injury. Confocal analysis of p62 distribution in the spinal dorsal horn indicated its presence mainly in NeuN-positive cell bodies and occasionally in glial processes, thus suggesting a predominant expression in the neuronal compartment. Finally, we investigated the consequences of autophagy impairment on pain behaviour by using the autophagy blocker cloroquine. Intrathecal chloroquine injection in naive mice induced spinal accumulation of LC3 and p62 paralleled by significant mechanical hypersensitivity thus confirming the block in autophagosome clearance and suggesting the participation of the autophagic process in spinal mechanisms of pain processing. Altogether, our data indicate that spinal autophagy is differentially altered in different experimental pain models of neuropathic pain and that this process may be relevant for pain control.
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Bergamot (Citrus bergamia, Risso et Poiteau) essential oil (BEO) is a well characterized, widely used plant extract. BEO exerts anxiolytic, analgesic and neuroprotective activities in rodents through mechanisms that are only partly known and need to be further investigated. To gain more insight into the biological effects of this essential oil, we tested the ability of BEO (0.005-0.03%) to modulate autophagic pathways in human SH-SY5Y neuroblastoma cells. BEO-treated cells show increased LC3II levels and appearance of dot-like formations of endogenous LC3 protein that colocalize with the lysosome marker LAMP-1. Autophagic flux assay using bafilomycin A1 and degradation of the specific autophagy substrate p62 confirmed that the observed increase of LC3II levels in BEO-exposed cells is due to autophagy induction rather than to a decreased autophagosomal turnover. Induction of autophagy is an early and not cell-line specific response to BEO. Beside basal autophagy, BEO also enhanced autophagy triggered by serum starvation and rapamycin indicating that the underlying mechanism is mTOR independent. Accordingly, BEO did not affect the phosphorylation of ULK1 (Ser757) and p70S6K (Thr389), two downstream targets of mTOR. Furthermore, induction of autophagy by BEO is beclin-1 independent, occurs in a concentration-dependent manner and is unrelated to the ability of BEO to induce cell death. In order to identify the active constituents responsible for these effects, the two most abundant monoterpenes found in the essential oil, d-limonene (125-750 µM) and linalyl acetate (62.5-375 µM), were individually tested at concentrations comparable to those found in 0.005-0.03% BEO. The same features of stimulated autophagy elicited by BEO were reproduced by d-limonene, which rapidly increases LC3II and reduces p62 levels in a concentration-dependent manner. Linalyl acetate was ineffective in replicating BEO effects; however, it greatly enhanced LC3 lipidation triggered by d-limonene.
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There are an estimated 35 million people with dementia across the world, of whom 50% experience regular pain. Despite this, current assessment and treatment of pain in this patient group are inadequate. In addition to the discomfort and distress caused by pain, it is frequently the underlying cause of behavioral symptoms, which can lead to inappropriate treatment with antipsychotic medications. Pain also contributes to further complications in treatment and care. This review explores four key perspectives of pain management in dementia and makes recommendations for practice and research. The first perspective discussed is the considerable uncertainty within the literature on the impact of dementia neuropathology on pain perception and processing in Alzheimer's disease and other dementias, where white matter lesions and brain atrophy appear to influence the neurobiology of pain. The second perspective considers the assessment of pain in dementia. This is challenging, particularly because of the limited capacity of self-report by these individuals, which means that assessment relies in large part on observational methods. A number of tools are available but the psychometric quality and clinical utility of these are uncertain. The evidence for efficient treatment (the third perspective) with analgesics is also limited, with few statistically well-powered trials. The most promising evidence supports the use of stepped treatment approaches, and indicates the benefit of pain and behavioral interventions on both these important symptoms. The fourth perspective debates further difficulties in pain management due to the lack of sufficient training and education for health care professionals at all levels, where evidence-based guidance is urgently needed. To address the current inadequate management of pain in dementia, a comprehensive approach is needed. This would include an accurate, validated assessment tool that is sensitive to different types of pain and therapeutic effects, supported by better training and support for care staff across all settings.
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Dementia has become an all-important disease because the population is aging rapidly and the cost of health care associated with dementia is ever increasing. In addition to cognitive function impairment, associated behavioral and psychological symptoms of dementia (BPSD) worsen patient's quality of life and increase caregiver's burden. Alzheimer's disease is the most common type of dementia and both behavioral disturbance and cognitive impairment of Alzheimer's disease are thought to be associated with the N-methyl-D-aspartate (NMDA) dysfunction as increasing evidence of dysfunctional glutamatergic neurotransmission had been reported in behavioral changes and cognitive decline in Alzheimer's disease. We review the literature regarding dementia (especially Alzheimer's disease), BPSD and relevant findings on glutamatergic and NMDA neurotransmission, including the effects of memantine, a NMDA receptor antagonist, and NMDA-enhancing agents, such as D-serine and D-cycloserine. Literatures suggest that behavioral disturbance and cognitive impairment of Alzheimer's disease may be associated with excitatory neurotoxic effects which result in impairment of neuronal plasticity and degenerative processes. Memantine shows benefits in improving cognition, function, agitation/aggression and delusion in Alzheimer's disease. On the other hand, some NMDA modulators which enhance NMDA function through the co-agonist binding site can also improve cognitive function and psychotic symptoms. We propose that modulating NMDA neurotransmission is effective in treating behavioral and psychological symptoms of Alzheimer's disease. Prospective study using NMDA enhancers in patients with Alzheimer's disease and associated behavioral disturbance is needed to verify this hypothesis.
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Nursing home residents with dementia gradually lose the ability to process information so that they are less likely to express pain in typical ways. These residents may express pain through disruptive behaviors because they cannot appropriately verbalize their pain experience. The objective of this study was to investigate the effect of pain on disruptive behaviors in nursing home residents with dementia. This is a secondary analysis of the Minimum Data Set (MDS 2.0) assessment data on long-term care from the state of Florida. The data used in this study were the first comprehensive assessment data from NH residents with dementia aged 65 and older (N = 56,577) in Medicare- or Medicaid-certified nursing homes between January 1, 2009 and December 31, 2009. Variables examined were pain, wandering, aggression, agitation, cognitive impairment, activities of daily living impairments, and demographic characteristics. Ordinal logistic regression was used to evaluate the effect of pain on disruptive behaviors. Residents with more severe pain are less likely to display wandering behaviors (OR = .77, 95% CI for OR = [0.73, 0.81]), but more likely to display aggressive and agitated behaviors (OR = 1.04, 95% CI for OR = [1.01, 1.08]; OR = 1.17, 95% CI for OR = [1.13, 1.20]). The relationship between pain and disruptive behaviors depends on the type of behaviors. Pain is positively correlated with disruptive behaviors that do not involve locomotion (e.g., aggression and agitation), but negatively related to disruptive behaviors that are accompanied by locomotion (e.g., wandering). These findings indicate that effective pain management may help to reduce aggression and agitation, and to promote mobility in persons with dementia.
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Many elderly people experience pain and regularly take analgesic medication. Pain is also frequent in people with dementia, particularly those with severe disease. As no robust clinical guidelines are available for the treatment of pain in the context of dementia, the risk of inadequate treatment in individuals with this condition is high. Furthermore, our understanding of the aetiology of pain and the potential role of dementia-associated neuropathology in pain is limited. These issues are important in the clinical management of individuals with dementia, as untreated pain is a major contributor to reduced quality of life and disability, and can lead to increased behavioural and psychological symptoms. Assessment scales to identify pain in people with dementia have been highlighted in recent studies, but there is little evidence for consistency between these tools. Numerous studies have evaluated various approaches for the treatment of pain, including stepped-care protocols and/or administration of paracetamol and opioid medications. In this Review, we summarize the best-available evidence regarding the aetiology, assessment and treatment of pain in people with dementia. Further validation of assessment tools and large-scale trials of treatment approaches in people with dementia are needed to improve clinical guidance for the treatment of pain in these individuals.
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Autophagy is an intracellular membrane trafficking pathway controlling the delivery of cytoplasmic material to the lysosomes for degradation. It plays an important role in cell homeostasis in both normal settings and abnormal, stressful conditions. It is now recognised that an imbalance in the autophagic process can impact basal cell functions and this has recently been implicated in several human diseases, including neurodegeneration and cancer. Here, we investigated the consequences of nerve injury on the autophagic process in a commonly used model of neuropathic pain. The expression and modulation of the main autophagic marker, the microtubule-associated protein 1 light chain 3 (LC3), was evaluated in the L4-L5 cord segment seven days after spinal nerve ligation (SNL). Levels of LC3-II, the autophagosome-associated LC3 form, were markedly higher in the spinal cord ipsilateral to the ligation side, appeared to correlate with the upregulation of the calcium channel subunit α2δ-1 and were not present in mice that underwent sham surgery. However, LC3-I and Beclin 1 expression were only slightly increased. On the contrary, SNL promoted the accumulation of the ubiquitin- and LC3-binding protein p62, which inversely correlates with autophagic activity, thus pointing to a block of autophagosome turnover. Our data showed for the first time that basal autophagy is disrupted in a model of neuropathic pain.
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Endocannabinoids (eCBs) are feedback messengers in the nervous system that act at the presynaptic nerve terminal to inhibit transmitter release. Here we report that in brain slices from rat, eCBs are released from vasopressin (VP) neurons in the paraventricular nucleus of the hypothalamus following coincident bursts of presynaptic and postsynaptic spiking. eCBs transiently depress glutamate release from excitatory terminals and, in doing so, prevent the synapses from undergoing long-term depression (LTD). Specifically, we show that blockade of CB1 receptors unmasks LTD following coincident presynaptic and postsynaptic activity. This LTD is presynaptic in nature, but requires the release of the opioid peptide dynorphin from the postsynaptic neuron. Dynorphin release and subsequent LTD require the activation of postsynaptic metabotropic glutamate receptors (mGluRs). Our findings indicate that eCBs, by transiently depressing glutamate release, limit mGluR activation and indirectly gate release of dynorphin from the postsynaptic neuron. We propose that eCBs, in addition to their well described role in the rapid modulation of transmitter release from the nerve terminal, also regulate the release of other retrograde transmitters and thus encode for multiple temporal windows of synaptic plasticity.
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Background: Repetitive C-fiber stimulation induces a state of facilitated processing of sensory information in the dorsal horn, while chronic nerve compression gives rise to a hyperalgesic state, characterized by spontaneous neuronal activity generated by voltage-sensitive sodium channels, as well as spinal facilitation. This study investigates the effects of systemic local anesthetic on thermal hyperalgesia evoked by chronic nerve compression and on the pain behavior responses to subcutaneous formalin. Methods: The effects of intravenous lidocaine were evaluated in rats with (1) the formalin test, a model of acute pain and centrally mediated delayed sensory sensitization, and (2) a model of chronic sciatic nerve compression leading to a neurogenic thermal hyperalgesia. Groups of rats (300 g) undergoing formalin testing were given intravenous lidocaine in doses of: 3 mg plus 25 mu g/min infusion (yielding serum levels of 6.3 +/- 1.0 mu g/ml) or 1.5 mg plus 12.5 mu g/min infusion (yielding serum levels of 3.6 +/- 0.3 mu g/ml) beginning 5 min before the subcutaneous injection of formalin In the left hind paw. In other studies, a group of six animals were rendered hyperalgesic in one hind limb by the placement of compressive ligatures about the left sciatic nerve (Bennett model) 3-5 days before these studies. These rats were treated with 0.6 mg intravenous lidocaine followed by an infusion of lidocaine at a rate of 5 mu g/min (yielding serum levels of 1.0 +/- 0.1 mu g/ml). Results: Lidocaine had no significant effect on the first phase of the formalin test or on thermal response latencies in normal limbs. However, at a high dose, lidocaine significantly reduced phase 2 flinching behavior and at a low dose, reversed the thermal hyperalgesia produced by sciatic nerve ligation during 30 min of infusion for a period of 3 h after the infusion was discontinued. Conclusions: Intravenous lidocaine acts by distinct mechanisms to diminish the hyperesthetic state induced by peripheral nerve injury and to reduce the degree of spinal sensitization induced by C-afferent fiber activation.
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Results: Of the 329 participants with dementia, 214 (65%) had Alzheimer’s disease, 62 (19%) had vascular dementia, and 53 (16%) had another DSM-IV dementia diagnosis; 201 (61%) had exhibited one or more mental or behavioral disturbances in the past month. Apathy (27%), depression (24%), and agitation/ aggression (24%) were the most com
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Agitation and aggression commonly arise in people with Alzheimer's disease (AD) and other dementias. They are distressing for the individual and often confer risk to them and to others, as well as raising significant clinical challenges. This review outlines the current evidence for pharmacological and nonpharmacological approaches to the treatment of agitation and aggression in these patients. There is a growing body of literature supporting the use of nonpharmacological approaches as well as the treatment of pain as a first-line management strategy prior to psychopharmacotherapy. Antipsychotic medications are most commonly prescribed to address agitation and aggression. Evidence indicates this approach results in a modest but significant improvement in aggression in the short term (6-12 weeks) although the impact on other symptoms of agitation is limited. There is less positive evidence to support their use in the longer term, and prescriptions of more than 12 weeks and longer periods of prescription are associated with cumulative risk of severe adverse events, including death. Suggested pharmacological alternatives with the most promising preliminary evidence include memantine, carbamazepine, citalopram, and prazosin, but none of these agents have sufficient evidence in treating agitation and aggression to recommend use in routine clinical practice. Currently, the best approach for managing these symptoms is within a framework of good practice that promotes prevention, monitoring and the use of nonpharmacological alternatives, with judicious short-term use of antipsychotics, when appropriate.
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Bergamot essential oil (BEO) is one of the most common essential oil containing linalool and linalyl acetate as major volatile components. This study investigated the effect of intraplantar (i.pl.) bergamot essential oil (BEO) or linalool on neuropathic hypersensitivity induced by partial sciatic nerve ligation (PSNL) in mice. The i.pl. injection of BEO or linalool into the ipsilateral hindpaw to PSNL reduced PSNL-induced mechanical allodynia in a dose-dependent manner. Peripheral (i.pl.) injection of BEO or linalool into the contralateral hindpaw did not yield anti-allodynic effects, suggesting a local anti-mechanical allodynic effect of BEO or linalool in PSNL mice. Anti-mechanical hypersensitivity of morphine was enhanced by the combined injection of BEO or linalool at an ineffective dose when injected alone. We also examined the possible involvement of spinal extracellular signal-regulated protein kinase (ERK) in BEO or linalool-induced anti-mechanical allodynia. In western blotting analysis, i.pl. injection of BEO or linalool resulted in a significant blockade of spinal ERK activation induced by PSNL. These results suggest that i.pl. injection of BEO or linalool may reduce PSNL-induced mechanical allodynia followed by decreasing spinal ERK activation.
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The use of complementary medicines, such as plant extracts, in dementia therapy varies according to the different cultural traditions. In orthodox Western medicine, contrasting with that in China and the Far East for example, pharmacological properties of traditional cognitive- or memory-enhancing plants have not been widely investigated in the context of current models of Alzheimer's disease. An exception is Gingko biloba in which the gingkolides have antoxidant, neuroprotective and cholinergic activities relevant to Alzheimer's disease mechanisms. The therapeutic efficacy of Ginkgo extracts in Alzheimer's disease in placebo controlled clinical trials is reportedly similar to currently prescribed drugs such as tacrine or donepezil and, importantly, undesirable side effects of Gingko are minimal. Old European reference books, such as those on medicinal herbs, document a variety of other plants such as Salvia officinalis (sage) and Melissa officinalis (balm) with memory-improving properties, and cholinergic activities have recently been identified in extracts of these plants. Precedents for modern discovery of clinically relevant pharmacological activity in plants with long-established medicinal use include, for example, the interaction of alkaloid opioids in Papaver somniferum (opium poppy) with endogenous opiate receptors in the brain. With recent major advances in understanding the neurobiology of Alzheimer's disease, and as yet limited efficacy of so-called rationally designed therapies, it may be timely to re-explore historical archives for new directions in drug development. This article considers not only the value of an integrative traditional and modern scientific approach to developing new treatments for dementia, but also in the understanding of disease mechanisms. Long before the current biologically-based hypothesis of cholinergic derangement in Alzheimer's disease emerged, plants now known to contain cholinergic antagonists were recorded for their amnesia- and dementia-inducing properties.
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Scand J Caring Sci; 2010; 24; 380–391 Pain in older persons with severe dementia. Psychometric properties of the Mobilization–Observation–Behaviour–Intensity–Dementia (MOBID-2) Pain Scale in a clinical setting Background: To assess pain in older persons with severe dementia is a challenge due to reduced self-report capacity. Recently, the development and psychometric property testing of the Mobilization–Observation–Behaviour–Intensity–Dementia (MOBID) Pain Scale was described using video-recording. The purpose of this article was to present the further development of this instrument. In MOBID-2 Pain Scale, the assessment of inferred pain intensity is based on patient’s pain behaviours in connection with standardized, guided movements of different body parts (Part 1). In addition, MOBID-2 includes the observation of pain behaviours related to internal organs, head and skin registered on pain drawings and monitored over time (Part 2). Objective: The aim of this study was to examine psychometric properties of the MOBID-2 Pain Scale, like inter-rater and test–retest reliability, internal consistency, as well as face-, construct- and concurrent validity. Subjects and Setting: Patients with severe dementia (n = 77) were examined by 28 primary caregivers in clinical practice, who concurrently and independently completed the MOBID-2 Pain Scale. Characteristics of the patients’ pain were also investigated by their physicians (n = 4). Results: Prevalence of any pain was 81%, with predominance to the musculoskeletal system, highly associated with the MOBID-2 overall pain score (rho = 0.82). Most frequent and painful were mobilizing legs. Pain in pelvis and/or genital organs was frequently observed. Moderate to excellent agreement was demonstrated for behaviours and pain drawings (κ = 0.41–0.90 and κ = 0.46–0.93). Inter-rater and test–retest reliability for pain intensity was very good, ICC (1, 1) ranging 0.80–0.94 and 0.60–0.94. Internal consistency was highly satisfactory; Cronbach’s α ranging 0.82–0.84. Face-, construct- and concurrent validity was good. Overall pain intensity by MOBID-2 was well correlated with physicians’ clinical examination and defined pain variables (rho = 0.41–0.64). Conclusion: On the basis of pain behaviours, standardized movements and pain drawings, MOBID-2 Pain Scale was shown to be sufficiently reliable, valid and time-effective for nurses to assess pain in patients with severe dementia.
Article
The generation of knock-out and transgenic mice offers a promising approach to the identification of novel biochemical factors that contribute to persistent pain conditions. To take advantage of these mice, however, it is important to demonstrate that the traditional models of persistent pain, which were largely developed for studies in the rat, can be used in the mouse. Here, we combined behavioral and anatomical methods to characterize the pathophysiology of a partial nerve injury-evoked pain condition in the `normal' mouse. In male C57BL6 mice we tied a tight ligature around 1/3 to 1/2 of the diameter of the sciatic nerve and evaluated the time-course and magnitude of the ensuing mechanical and thermal allodynia. We also used immunocytochemistry to analyze nerve injury-induced changes in substance P (SP) and NK-1 (SP) receptor expression in the spinal cord. As in the rat, partial nerve injury markedly decreased paw withdrawal thresholds to both mechanical and thermal stimuli on the injured side. We detected threshold changes one day after the injury. The thermal allodynia resolved by 49 days, but the mechanical allodynia persisted for the duration of the study (70 days). We found no changes contralateral to the nerve injury. Sympatholytic treatment with guanethidine significantly reduced both the thermal and mechanical allodynia. We observed a reduction of SP immunoreactivity in the superficial dorsal horn on the injured side at 7 and 14, but not at 3 or 70 days after the nerve injury, and we observed an increase of NK-1 receptor expression at 3, 7, 14 and 42, but not at 70 days after the injury. We conclude that partial injury to the sciatic nerve produces a comparable allodynia and neurochemical plasticity in the rat and mouse. These results establish a valuable model for future studies of the biochemical basis of neuropathic pain in mice with specific gene modifications.
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A novel test for the selective identification of anxiolytic and anxiogenic drug effects in the rat is described, using an elevated + -maze consisting of two open arms and two enclosed arms. The use of this test for detecting such drug effects was validated behaviourally, physiologically, and pharmacologically. Rats made significantly fewer entries into the open arms than into the closed arms, and spent significantly less time in open arms. Confinement to the open arms was associated with the observation of significantly more anxiety-related behaviours, and of significantly greater plasma corticosterone concentrations, than confinement to the closed arms. Neither novelty nor illumination was a significant contributor to the behaviour of the rats on the + -maze. A significant increase in the percentage of time spent on the open arms and the number of entries into the open arms was observed only within clinically effective anxiolytics (chlordiazepoxide, diazepam and, less effectively, phenobarbitone). Compounds that cause anxiety in man significantly reduced the percentage of entries into, and time spent on, the open arms (yohimbine, pentylenetetrazole, caffeine, amphetamine). Neither antidepressants nor major tranquilisers had a specific effect. Exposure to a holeboard immediately before placement on the + -maze showed that behaviour on the maze was not clearly correlated either with exploratory head-dipping or spontaneous locomotor activity.
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The chemical composition of the widely used herbal tea made from lemon balm (Melissa officinalis L. subsp. officinalis) was previously unknown. The qualitative and quantitative composition of the main aromatic and polyphenolic constituents of the infusion were examined and compared with those of the leaves before and after infusion. The dried lemon balm leaves originally contained 0.32% essential oil of which citral (neral + geranial) 0.13%, total polyphenol compounds 11.8% comprising total hydroxycinnamic compounds 11.3% (rosmarinic acid 4.1%) and total flavonoid compounds 0.5%. The tea contained 10 mg/l of essential oil (extraction yield 31%) with much more citral (74% of the essential oil). It also contained large amounts of polyphenol compounds (about 1.07 g/l) corresponding to a 93% extraction yield.
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A new scoring technique is described that measures active behaviors of rats in the forced swimming test, a test that predicts antidepressant drug effects. The technique distinguishes the effects of selective serotonin reuptake inhibitors, which reduce immobility and increase swimming behavior, from selective norepinephrine reuptake inhibitors, which reduce immobility and increase climbing behavior. The magnitude of behavioral effects described for each drug (i.e., reduced immobility for both drugs, increased swimming for fluoxetine, increased climbing for desipramine) was greater when testing was conducted at the deeper 30-cm rather than the shallow 15-cm water depth. Results obtained with the technique demonstrate that selective serotonin reuptake inhibitors are not false negatives in the rat forced swimming test, as previously thought.
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Injection of formalin in the rat hindpaw produces two phases of nociceptive behavior. Although it is generally agreed that the first phase results from direct chemical activation of nociceptive primary afferent fibers, the factors that contribute to the second phase are not established. In the present study, we monitored the expression of the c-fos protein to evaluate whether the pattern of activity of dorsal horn neurons differs as a result of ongoing afferent activity during the two phases. To selectively block the first or second phase, we respectively used remifentanil, a potent and short acting opiate agonist, and QX-314, a quaternary derivative of lidocaine, which does not cross the blood brain barrier. We also evaluated the effect of eliminating nociceptive behavior in both phases using both remifentanil and lidocaine or a combination of local anesthetics, bupivicaine and quaternary lidocaine. In all groups, formalin (5%, 50 μl) was injected subcutaneously into the plantar surface of the hindpaw. To assess the nociceptive behavior produced by formalin, we monitored the number of flinches. Injection of remifentanil during the first phase completely blocked the first phase formalin-evoked nociceptive behavior, and had no effect on the second phase. Injection of lidocaine during the interphase completely blocked second phase nociceptive behavior. As expected, when remifentanil was administered during the first phase and lidocaine during the second phase, all formalin-evoked nociceptive behavior was blocked. The same was true for rats that received injections of bupivicaine and lidocaine during phases 1 and 2, respectively. In laminae I–II of the L4–L5 segment, the magnitude of the decrease in Fos expression was comparable for remifentanil (26.5%) and lidocaine (27.3%); the decrease was greater when both remifentanil and lidocaine were administered (50.5%), and even greater when bupivicaine and lidocaine were used (74.2%). In laminae V–VI, remifentanil, by itself, decreased c-fos expression by 39.4%; for lidocaine alone, the decrease was 58.4%. We did not observe further significant decreases when both remifentanil and lidocaine, or bupivacaine and lidocaine were injected (69.7% and 74.6%, respectively). Our results not only provide strong evidence that activity during the second phase is necessary for maintaining the maximal expression of c-fos in the spinal cord, but also reveal significant regional differences in the central patterns of activity generated during the two phases. These results also confirm our previous reports that c-fos expression is not eliminated when the behavioral manifestation of the noxious stimulus is completely blocked.
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The etiology of behavioral and psychiatric symptoms is generally considered to be multifactorial, and these symptoms often indicate a need for care or assistance, which may include the presence of uncontrolled pain. The aim of this cross-sectional study was to assess the association of pain with behavioral and psychiatric symptoms in a population of nursing home (NH) residents with cognitive impairment in Europe. Data are from the SHELTER project, which contains information on NH residents in 8 countries. Pain was defined as any type of physical pain or discomfort in any part of the body in the 3 days before the assessment. The mean age of 2822 cognitively impaired residents entering the study was 84.1 (standard deviation 9.1)years, and 2110 (74.8%) were women. Of the total sample, 538 residents (19.1%) presented with pain. After adjusting for potential confounders, pain was significantly and positively associated with socially inappropriate behavior (odds ratio [OR] 1.37; 95% confidence interval [CI] 1.04-1.80), resistance to care (OR 1.41; 95% CI 1.08-1.83), abnormal thought process (OR 1.48; 95% CI 1.16-1.90), and delusions (OR 1.48; 95% CI 1.07-2.03). A borderline inverse association was observed with wandering (OR 0.74; 95% CI 0.55-1.00). In conclusion, this cross-sectional study provides evidence from a large sample of frail elderly showing an association between pain and behavioral and psychiatric symptoms. Treatment models that put together assessment and treatment of pain and evaluate their effect on behavioral and psychiatric symptoms are needed.
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The effects of bergamot essential oil (BEO; Citrus bergamia, Risso) on excitotoxic neuronal damage was investigated in vitro. The study was performed in human SH-SY5Y neuroblastoma cells exposed to N-methyl-D-aspartate (NMDA). Cell viability was measured by dye exclusion. Reactive oxygen species (ROS) and caspase-3 activity were measured fluorimetrically. Calpain I activity and the activation (phosphorylation) of Akt and glycogen synthase kinase-3beta (GSK-3beta) were assayed by Western blotting. NMDA induced concentration-dependent, receptor-mediated, death of SH-SY5Y cells, ranging from 11 to 25% (0.25-5 mM). Cell death induced by 1 mM NMDA (21%) was preceded by a significant accumulation of intracellular ROS and by a rapid activation of the calcium-activated protease calpain I. In addition, NMDA caused a rapid deactivation of Akt kinase and this preceded the detrimental activation of the downstream kinase, GSK-3beta. BEO (0.0005-0.01%) concentration dependently reduced death of SH-SY5Y cells caused by 1 mM NMDA. In addition to preventing ROS accumulation and activation of calpain, BEO (0.01%) counteracted the deactivation of Akt and the consequent activation of GSK-3beta, induced by NMDA. Results obtained by using specific fractions of BEO, suggested that monoterpene hydrocarbons were responsible for neuroprotection afforded by BEO against NMDA-induced cell death. Our data demonstrate that BEO reduces neuronal damage caused in vitro by excitotoxic stimuli and that this neuroprotection was associated with prevention of injury-induced engagement of critical death pathways.
Article
This study investigated the effect of bergamot essential oil (BEO) containing linalool and linalyl acetate as major volatile components in the capsaicin test. The intraplantar injection of capsaicin (1.6 μg) produced a short-lived licking/biting response toward the injected paw. The nociceptive behavioral response evoked by capsaicin was inhibited dose-dependently by intraplantar injection of BEO. Both linalool and linalyl acetate, injected into the hindpaw, showed a significant reduction of nociceptive response, which was much more potent than BEO. Intraperitoneal (i.p.) and intraplantar pretreatment with naloxone hydrochloride, an opioid receptor antagonist, significantly reversed BEO- and linalool-induced antinociception. Pretreatment with naloxone methiodide, a peripherally acting μ-opioid receptor preferring antagonist, resulted in a significant antagonizing effect on antinociception induced by BEO and linalool. Antinociception induced by i.p. or intrathecal morphine was enhanced by the combined injection of BEO or linalool. The enhanced effect of combination of BEO or linalool with morphine was antagonized by pretreatment with naloxone hydrochloride. Our results provide evidence for the involvement of peripheral opioids, in the antinociception induced by BEO and linalool. Combined administration of BEO or linalool acting at the peripheral site, and morphine may be a promising approach in the treatment of clinical pain.
Article
Recently, the importance of non-pharmacological therapies for dementia has come to the fore. In the present study, we examined the curative effects of aromatherapy in dementia in 28 elderly people, 17 of whom had Alzheimer's disease (AD). After a control period of 28 days, aromatherapy was performed over the following 28 days, with a wash out period of another 28 days. Aromatherapy consisted of the use of rosemary and lemon essential oils in the morning, and lavender and orange in the evening. To determine the effects of aromatherapy, patients were evaluated using the Japanese version of the Gottfries, Brane, Steen scale (GBSS-J), Functional Assessment Staging of Alzheimer's disease (FAST), a revised version of Hasegawa's Dementia Scale (HDS-R), and the Touch Panel-type Dementia Assessment Scale (TDAS) four times: before the control period, after the control period, after aromatherapy, and after the washout period. All patients showed significant improvement in personal orientation related to cognitive function on both the GBSS-J and TDAS after therapy. In particular, patients with AD showed significant improvement in total TDAS scores. Result of routine laboratory tests showed no significant changes, suggesting that there were no side-effects associated with the use of aromatherapy. Results from Zarit's score showed no significant changes, suggesting that caregivers had no effect on the improved patient scores seen in the other tests. In conclusion, we found aromatherapy an efficacious non-pharmacological therapy for dementia. Aromatherapy may have some potential for improving cognitive function, especially in AD patients.
Article
Bergamot (Citrus bergamia, Risso) is a fruit most knowledgeable for its essential oil (BEO) used in aromatherapy to minimize symptoms of stress-induced anxiety and mild mood disorders and cancer pain though the rational basis for such applications awaits to be discovered. The behavioural and EEG spectrum power effects of BEO correlate well with its exocytotic and carrier-mediated release of discrete amino acids endowed with neurotransmitter function in the mammalian hippocampus supporting the deduction that BEO is able to interfere with normal and pathological synaptic plasticity. The observed neuroprotection in the course of experimental brain ischemia and pain does support this view. In conclusion, the data yielded so far contribute to our understanding of the mode of action of this phytocomplex on nerve tissue under normal and pathological experimental conditions and provide a rational basis for the practical use of BEO in complementary medicine. The opening of a wide venue for future research and translation into clinical settings is also envisaged.
Article
Bergamot (Citrus bergamia Risso et Poiteau) is a citrus fruit growing almost exclusively in the South of Italy. Its essential oil is obtained by cold pressing of the epicarp and, partly, of the mesocarp of the fresh fruit. Although this phytocomplex has been used for centuries, reputedly effectively, as a traditional medicine, there is very little verified scientific evidence to support this use. This paper reports original data on the systemic effects of the essential oil of bergamot (BEO) on gross behaviour and EEG activity recorded from the hippocampus and cerebral cortex of the rat. The Fast Fourier Transformation (FFT) was used to analyse and quantify the energy in single frequency bands of the EEG spectrum. The results obtained indicate that systemic administration of increasing volumes of BEO produces dose-dependent increases in locomotor and exploratory activity that correlate with a predominant increase in the energy in the faster frequency bands of the EEG spectrum. These data contribute to our understanding of the neurobiological profile of BEO.
Article
The plant Melissa officinalis L. has been used traditionally in the treatment of cognitive dysfunction. Based on its traditional medicinal use, it was assessed for its clinical efficacy in mild to moderate Alzheimer's patients. The plant was effective in the management of the disease. Therefore, based on this result, a similar plant extract was prepared in order to be screened for bioactivities which are relevant in Alzheimer's disease therapy. The extract was recently screened for antioxidant activity and it showed a wide range of antioxidant properties. Another important bioactivity is acetylcholinesterase inhibition, which the extract was screened for in the current investigation. The extract was capable of inhibiting the enzyme in a time and dose-dependent manner. Activity of the extract at 10 min was estimated as 1.72+/-0.16 microg equivalents of physostigmine/mg of the extract. Acetylcholinesterase inhibitory guided fractionation of the extract was then carried out. Most of the fractions showed inhibitory activity and were more potent than the extract. The contents of the most potent fraction were identified as cis- and trans-rosmarinic acid isomers and a rosmarinic acid derivative using LC-DAD-ESI-MS and NMR methods.
Article
Rats and mice when forced to swim in a restricted space will rapidly cease attempts to escape and become immobile. Previous experiments have shown that immobility was selectively reduced by antidepressant agents. The present experiments show that important differences exist between strains in both the amount of immobility observed and the effects of imipramine. Strain differences should therefore be taken into account in attempts to replicate results from one laboratory to another.
Article
We attempted to develop an experimental animal model for peripheral neuropathic pain. Under sodium pentobarbital anesthesia, both the L5 and L6 spinal nerves (group 1) or the L5 spinal nerve alone (group 2) of one side of the rat were tightly ligated. For comparison, a parallel study was conducted with another group of rats (group 3) which received a partial tight sciatic nerve ligation, a paradigm developed previously as a neuropathy model. Withdrawal latencies to application of radiant heat to the foot were tested for the next 16 weeks in all 3 groups. Sensitivity of the hind paw to mechanical stimulation was tested with von Frey filaments. The general behavior of each rat was noted during the entire test period. Results suggested that the surgical procedure in all 3 groups produced a long-lasting hyperalgesia to noxious heat (at least 5 weeks) and mechanical allodynia (at least 10 weeks) of the affected foot. In addition, there were behavioral signs of the presence of spontaneous pain in the affected foot. Therefore, we believe we have developed an experimental animal model for peripheral neuropathy using tight ligations of spinal nerves. The model manifests the symptoms of human patients with causalgia and is compatible with a previously developed neuropathy model. The present model has two unique features. First, the surgical procedure is stereotyped. Second, the levels of injured and intact spinal segments are completely separated, allowing independent experimental manipulations of the injured and intact spinal segments in future experiments to answer questions regarding mechanisms underlying causalgia.
Article
Eighty-three brains obtained at autopsy from nondemented and demented individuals were examined for extracellular amyloid deposits and intraneuronal neurofibrillary changes. The distribution pattern and packing density of amyloid deposits turned out to be of limited significance for differentiation of neuropathological stages. Neurofibrillary changes occurred in the form of neuritic plaques, neurofibrillary tangles and neuropil threads. The distribution of neuritic plaques varied widely not only within architectonic units but also from one individual to another. Neurofibrillary tangles and neuropil threads, in contrast, exhibited a characteristic distribution pattern permitting the differentiation of six stages. The first two stages were characterized by an either mild or severe alteration of the transentorhinal layer Pre-alpha (transentorhinal stages I-II). The two forms of limbic stages (stages III-IV) were marked by a conspicuous affection of layer Pre-alpha in both transentorhinal region and proper entorhinal cortex. In addition, there was mild involvement of the first Ammon's horn sector. The hallmark of the two isocortical stages (stages V-VI) was the destruction of virtually all isocortical association areas. The investigation showed that recognition of the six stages required qualitative evaluation of only a few key preparations.
Article
Out of a sample of 178 patients with AD, aggression was present in 20%, wandering in 19%, binge-eating in 10%, hyperorality in 6%, urinary incontinence in 48%, and sexual disinhibition in 7%. Behavioural abnormalities were greater in those with more severe dementia. Temporallobe atrophy correlated with aggression, and widening of the third ventricle with hyperorality. Features of the Kluver-Bucy syndrome were commonly seen, but the full syndrome occurred in only one subject. Patients with at least one feature of the Kluver-Bucy syndrome had greater temporal-lobe atropy than those without any of the features.
Article
Of 178 patients with AD, at least one depressive symptom was reported by 63%, 24% were rated as being depressed by a trained observer, and 43% were considered depressed by their relatives. Ten per cent had a previous history of depression. Elevated mood was rare, occurring in only six patients (3.5%). Subjects with depressive symptoms had less cognitive impairment and less ventricular enlargement on CT compared with those without symptoms. Widening of the interhemispheric fissure was associated with symptoms of mania but was inversely related to presence of depressive symptoms.