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The role of the vanilloid (capsaicin) receptor (TRPV1) in physiology and pathology
Abstract
The cloning of the vanilloid receptor 1 opened a floodgate for discoveries regarding the function of this complex molecule. It has been found that, in addition to heat, protons and vanilloids, this receptor also responds to various endogenous ligands. Furthermore, it has been also emerged that, through associations with other molecules, the vanilloid receptor 1 plays an important role in the integration of various stimuli and modulation of cellular excitability. Although, originally, the vanilloid receptor 1 was associated with nociceptive primary afferent fibres, it has been gradually revealed that it is broadly expressed in the brain, epidermis and visceral cells. The expression pattern of the vanilloid receptor 1 indicates that it could be involved in various physiological functions and in the pathomechanisms of diverse diseases. Here, we summarise the molecular, pharmacological and physiological characteristics, and putative functions, of the vanilloid receptor 1, and discuss the therapeutic potential of this molecule.
... TRPV1 is known for its role as a mediator of pain and heat sensation 3 . Its endogenous ligands are protons, ATP, anandamide, dopamines and lipoxygenase products 26 . Structure analyses show that the channel forms a homotetramer, consisting of six transmebrane domains with intracellular localization of both C-and N-terminus. ...
... TRPV1 mediates many different effects in the cardiovascular system, being both protective and harmful, depending on the precise setting: TRPV1 was shown to mediate ventricular hypertrophy and to aggravate arterial hypertension and pulmonary hypertension, but on the other side to protect the myocardium from reperfusion injury 27 . In different organ systems, the participation of TRPV1 in inflammatory processes has become apparent, for example in inflammatory bowel diseases 28 or neurogenic inflammatory diseases 26 . The precise role of TRPV1 for regular cardiomyocyte function is not established so far, but the presence of TRPV1 in cardiac muscle, more precisely, at costameres, Table 2. Intracellular pathway signaling by phosphorylation of JNK, ERK and p38 after TRPV1 stimulation or inhibition in hiPSC-derived cardiomyocytes. ...
... We demonstrate that TRPV1 has a significant function for myocardial injury imposed by bacterial infection. The observation of the interference of an agonist with the effects of a pro-inflammatory agent might become important in the future, as capsaicin-derived compounds are already being used for treatment of neurogenic inflammatory pain in cutaneous diseases, headaches or neurogenic diseases 26 . Further studies are needed to specify the role of TRPV1 agonists or antagonists for immunomodulation in the clinical setting and to study their long-term side effects on the cardiovascular system. ...
The non-selective cation channel transient receptor potential vanilloid 1 (TRPV1) is expressed throughout the cardiovascular system. Recent evidence shows a role for TRPV1 in inflammatory processes. The role of TRPV1 for myocardial inflammation has not been established yet. Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (hiPSC-CM) from 4 healthy donors were incubated with lipopolysaccharides (LPS, 6 h), TRPV1 agonist capsaicin (CAP, 20 min) or the antagonist capsazepine (CPZ, 20 min). TRPV1 expression was studied by PCR and western blotting. TRPV1 internalization was analyzed by immunofluorescence. Interleukin-6 (IL-6) secretion and phosphorylation of JNK, p38 and ERK were determined by ELISA. TRPV1-associated ion channel current was measured by patch clamp. TRPV1-mRNA and -protein were expressed in hiPSC-CM. TRPV1 was localized in the plasma membrane. LPS significantly increased secretion of IL-6 by 2.3-fold, which was prevented by pre-incubation with CPZ. LPS induced TRPV1 internalization. Phosphorylation levels of ERK, p38 or JNK were not altered by TRPV1 stimulation or inhibition. LPS and IL-6 significantly lowered TRPV1-mediated ion channel current. TRPV1 mediates the LPS-induced inflammation in cardiomyocytes, associated with changes of cellular electrophysiology. LPS-induced inflammation results in TRPV1 internalization. Further studies have to examine the underlying pathways and the clinical relevance of these findings.
... The C-fibers transmit pain messages to the superficial Rexed's laminae of the medulla's dorsal horn and then to the spinothalamic tract. Prolonged activation of these cutaneous TRPV1 receptors triggers a calcium-mediated desensitization mechanism in the TRPV1 receptors and local C-fibers, leading to local elevation of the pain threshold for an extended time [27]. Significant pain relief has been demonstrated on localized neuropathic pain, such as postherpetic neuralgia, post-HIV neuralgia, and diabetic neuropathy [28,29]. ...
... This could partly be explained by one of the taxane-linked CIPN induction mechanisms, with TRPV1 receptor overexpression in sensitive neuronal soma in the dorsal root ganglia through prolonged activation of glutamate receptors, inducing hyperalgesia [37,38]. Local HCCP applications may then desensitize those sensitive neurons upstream [27]. ...
Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is often painful and can arise during or after the end of oncological treatments. They are mostly induced by platinum salts, taxanes, and immunotherapies. Their incidence is estimated between 19 and 85%. They can require a chemotherapy dose reduction or early termination. The European Society for Medical Oncology (ESMO) recommends high-concentration capsaicin patch (HCCP) in second line for the treatment of painful CIPN. This treatment induces a significative pain relief but only shown by low-powered studies. The objective of this study was to evaluate efficacy and tolerability of HCCP applications in CIPN. Methods: This monocentric observational retrospective real-world-data study of the CERCAN cohort took place in the Western Cancer Institute’s Anaesthesiology and Pain Department at Angers, France. Independent pain physicians completed the CGIC (Clinician Global Impression of Change) for each patient who benefited from HCCP applications for painful CIPN starting from 1 January 2014 to 22 December 2021, based on the collected data after every patch application. Results: A total of 57 patients (80.7% women) was treated with HCCP for painful CIPN, and 184 applications were realized, consisting of 296 sessions. CGIC found an important or complete pain relief for 61 applications (33.2%, corresponding to 43.9% patients). We found less efficacy for platinum-salts-induced CIPN compared to others (p = 0.0238). The efficacy was significatively higher for repeated applications when HCCP was used in second line compared to third line (p = 0.018). The efficacy of HCCP was significatively higher starting the third application (p = 0.0334). HCCPs were mainly responsible for local adverse events found in 66.6% patients (65.1% burning or painful sensation, 21.1% erythema). Conclusion: HCCP applications in painful CIPN induce an important pain relief with a global satisfying tolerability.
... In addition, different animal studies have shown using capsaicin injections in neonatal rats that this molecule induces its effect through TRPV1 [164]. This receptor is implicated in different pathological symptoms, such as pain, visceral hyperreflexia, and neurogenic inflammation [165]. Recently, Kishimoto et al. demonstrated that chronic intermittent hypoxia could be responsible for pain on the ocular surface via TRPV1-dependent mechanisms [166]. ...
... A lot of studies have shown that TRPV1 is highly implicated in the underlying mechanisms of peripheral sensitization [165,167,168]. TRPV1 −/− mice present abnormal nociceptive, inflammatory, and hypothermic responses to vanilloid compounds. ...
Dry eye disease (DED) is a multifactorial disorder in which the eyes respond to minor stimuli with abnormal sensations, such as dryness, blurring, foreign body sensation, discomfort, irritation, and pain. Corneal pain, as one of DED’s main symptoms, has gained recognition due to its increasing prevalence, morbidity, and the resulting social burden. The cornea is the most innervated tissue in the body, and the maintenance of corneal integrity relies on a rich density of nociceptors, such as polymodal nociceptor neurons, cold thermoreceptor neurons, and mechano-nociceptor neurons. Their sensory responses to different stimulating forces are linked to the specific expression of transient receptor potential (TRP) channels. TRP channels are a group of unique ion channels that play important roles as cellular sensors for various stimuli. These channels are nonselective cation channels with variable Ca2+ selectivity. TRP homologs are a superfamily of 28 different members that are subdivided into 7 different subfamilies based on differences in sequence homology. Many of these subtypes are expressed in the eye on both neuronal and non-neuronal cells, where they affect various stress-induced regulatory responses essential for normal vision maintenance. This article reviews the current knowledge about the expression, function, and regulation of TRPs in ocular surface tissues. We also describe their implication in DED and ocular pain. These findings contribute to evidence suggesting that drug-targeting TRP channels may be of therapeutic benefit in the clinical setting of ocular pain.
... The use of the selective sensory neurotoxin capsaicin (Jancsó et al. 1977;Jancsó and Király 1981;Jancsó et al. 2012), a TRPV1 agonist (Caterina et al. 1997) proved to be a relia b l e e x p e r i m e n t a l a p p r o a c h f o r t h e s e l e c t i v e defunctionalization or even elimination of C-fiber afferent nerve fibers (Jancsó et al. 1977;Chung et al. 1985;Ritter and Dinh 1988). Systemic or local administration of capsaicin produces a rather selective loss of C-fiber primary afferent neurons and/or spinal primary afferents (Jancsó et al. 1977;Fitzgerald and Woolf 1982;Nagy and Hunt 1983;Jancsó and Lawson 1990;Pini et al. 1990;Holzer 1991;Nagy et al. 2004;Jancsó et al. 2012). Indeed, following a systemic administration of capsaicin to newborn rats, up to 95% of unmyelinated axons are lost in spinal dorsal roots (Nagy and Hunt 1983). ...
... Hence, these data clearly indicate that the selective neurotoxic effect of capsaicin on C-fiber primary sensory neurons can be exploited to study the participation of this particular class of neurons in physiological and pathological processes. In fact, in the past decades, hundreds of studies utilized this approach to study the contribution of capsaicin-sensitive C-fiber primary sensory neurons to nociceptive and other homeostatic functions (for reviews, see, e.g., Buck and Burks 1986;Maggi and Meli 1988;Szállási and Blumberg 1990;Holzer 1991;Szolcsányi 1996;Nagy et al. 2004;Jancsó and Sántha 2015). Previous studies furnished circumstantial evidence for the role of activation of myelinated but not unmyelinated sensory nerve fibers in the development of spinal microgliosis associated with peripheral nerve injury (Suter et al. 2009). ...
Peripheral nerve injury is associated with spinal microgliosis which plays a pivotal role in the development of neuropathic pain behavior. Several agents of primary afferent origin causing the microglial reaction have been identified, but the type(s) of primary afferents that release these mediators are still unclear. In this study, specific labeling of C-fiber spinal afferents by lectin histochemistry and selective chemodenervation by capsaicin were applied to identify the type(s) of primary afferents involved in the microglial response. Comparative quantitative morphometric evaluation of the microglial reaction in central projection territories of intact and injured peripheral nerves in the superficial (laminae I and II) and deep (laminae III and IV) spinal dorsal horn revealed a significant, about three-fold increase in microglial density after transection of the sciatic or the saphenous nerve. Prior perineural treatment of these nerves with capsaicin, resulting in a selective defunctionalization of C-fiber afferent fibers failed to affect spinal microgliosis. Similarly, peripheral nerve injury-induced increase in microglial density was unaffected in rats treated neonatally with capsaicin known to result in a near-total loss of C-fiber dorsal root fibers. Perineural treatment with capsaicin per se did not evoke a significant increase in microglial density. These observations indicate that injury-induced spinal microgliosis may be attributed to phenotypic changes in injured myelinated primary afferent neurons, whereas the contribution of C-fiber primary sensory neurons to this neuroimmune response is negligible. Spinal myelinated primary afferents may play a hitherto unrecognized role in regulation of neuroimmune and perisynaptic microenvironments of the spinal dorsal horn.
... 9 Endogenous TRPV1 agonists i.e capsaicin and modulators such as protons, anandamide and products of the arachidonic acid metabolism can be released or up-regulated by inflammation and tissue damage. 15,16,17 Preclinically, disruption of the TRPV1 gene suggests that TRPV1 receptors are essential for inflammatory hyperalgesia. 14 These and other published studies have suggested a potential therapeutic utility of TRPV1 antagonists in pain. ...
... Our linings are also supported by the researchers i.e endocannabinoids are also endogenous ligand for TRPV1. 15,16,17 Moreover CB1 gets downregulated and its antinociceptive properties during chronic alcoholism gets impaired. 22 On the basis of the above discussion it may be concluded that TRPV1 receptor is involved in development of alcoholic neuropathic pain in rats, and endocannabinnoids may be responsible for its activation. ...
Alcoholic neuropathy is caused due to long term consumption of alcohol which leads to degeneration of neurons consequently, leading to neuropathic pain. Trpv1 is a ligand gated channel which gets activated in chronic alcoholism. The present research work. has been design to investigate the involvement of endocannabinoids in the activation of TRPV1 receptor in neuropathic pain during chronic alcoholism in wistar rat. The drugs capsazepine (1mg/kg i.p), a TRPV1 receptor antagonist, tetrahydrolipstatin (12mg/kg i.p), endogenous cannabinoid biosynthesis inhibitor, were given alone as well as in combination, one week before the peak nociception alcoholic rats. Capsaicin (0.1mg/kg i.p), TRPV1receptor agonist were administered for one week after the administration of capsazepine (1mg/kg i.p) in alcoholic rats. Pain were assessed with the help of Eddy's hot plate, Tail flick method and Tail immersion method. After applied found to be decreasing in alcoholing control group as compared to normal control group. Decrease in pain threshold was obtained in animals which were administered alcohol twice daily.
... Pharmacological, neurochemical and immunohistochemical studies have revealed that many of these sensoryefferent or local regulatory functions of chemosensitive PSNs are mediated by neuropeptides released from the stimulated sensory nerve endings. Hence, the dual functional character of chemosensitive PSNs, first envisaged and proved by N. Jancsó (Jancsó, 1960;Jancsó et al., 1968) has been amply confirmed and supported by a vast body of experimental data (for reviews see Holzer, 1988;Maggi and Meli, 1988;Szolcsányi, 1996;Nagy et al., 2004;Jancsó et al., 2009). ...
... Studies conducted in the past two decades have revealed that TRPV1 is the archetypal nociceptive ion channel functioning as a molecular integrator of noxious stimuli (Nagy et al., 2004;Gold and Caterina, 2007;Julius, 2013). Henceforth, any new information as regards the neurochemical features of TRPV1-expressing PSNs may point to novel ways to interfere with TRPV1 function including the transmission of painful stimuli and local modulation of organ functions. ...
... The action of capsaicin is mediated by Transient receptor potential vanilloid "TRPV1" (vanilloid receptor), which belongs to an ion channel group. Not only capsaicin but also heat, proton, and Resiniferatoxin (RTX) can activate this receptor leading to many physiological effects (Szallasi &Blumberg 1999 andNagy et al., 2004). Akiba et al. (2004) reported that the discovery of TPRV1 on the beta cells of pancreas and found that capsaicin could activate this receptor resulting in an increase in insulin secretion. ...
... The action of capsaicin is mediated by TPRV1 (vanilloid receptor), which belongs to an ion channel group. Not only capsaicin but also heat, proton, and Resiniferatoxin (RTX) can activate this receptor leading to many physiological effects (Szallasi &Blumberg, 1999 andNagy et al., 2004). Akiba et al. (2004) reported the discovery of TPRV1 on the beta cells of pancreas and found that capsaicin could activate this receptor resulting in an increase in insulin secretion. ...
This study investigated the effect of different drying methods, such as
solar drying at 45oC and conventional drying at 60oC on the quality of red
chili pepper for two varieties Serrano and Fresno. There were no significant
difference between drying methods effects on chemical composition of the
two varieties Serrano and Fresno with the exception of moisture which
decreased in conventional dried samples more than solar. Meanwhile, the
conventional drying method had the highest capsaicin content extracted by
ethanol (2.74 and 1.28 %) for Serrano and Fresno varieties respectively. The
antioxidant activity of fresh red chili pepper recorded the highest values
(95.32 and 90.67 %). The effect of dried red chili pepper at 1 and 2% and the
pure capsaicin at 0.015% were studied in experiments using male albino rats
containing 20 % high fat diet (HFD) rendered diabetic with alloxan injection
for 4 weeks. The lowest value of blood serum glucose was with G4 that fed
HFD + 0.015% capsaicin that recorded 160 mg/dl. Moreover, serum
cholesterol as well as serum triglycerides for the diabetic groups G4 and also
G6 “fed HFD + 2% Serrano red dried chili pepper” were significantly low.
The HDL concentration for the groups G4 and G6 were significantly higher
than the G3 diabetic rats fed with HFD. Feeding the groups of diabetic rats
with HFD + 1 or 2% dried red chili pepper or 0.015% capsaicin, the LDL and
VLDL levels as well as total lipids were significantly low as compared with
control diabetic HFD “G3”. The histopathological examination of liver and
pancreas show that G4 and G6 of diabetic rats fed HFD, either administerated
with 0.015 % capsaicin or fed with diet containing 2% dried Serrano pepper
had the best histological examination for liver or pancreas. The chemical
composition of all prepared chicken patty samples were almost the same,
meanwhile, the chicken patty samples containing 2 % Serrano pepper show
the best results for all physical and microbiological examination as well as
sensory evaluation.
Keywords: Red chili, Capsicum annum, capsaicin, drying, type 2 diabetes,
cholesterol, high fat diet, chicken patties
... The action of capsaicin is mediated by Transient receptor potential vanilloid "TRPV1" (vanilloid receptor), which belongs to an ion channel group. Not only capsaicin but also heat, proton, and Resiniferatoxin (RTX) can activate this receptor leading to many physiological effects (Szallasi &Blumberg 1999 andNagy et al., 2004). Akiba et al. (2004) reported that the discovery of TPRV1 on the beta cells of pancreas and found that capsaicin could activate this receptor resulting in an increase in insulin secretion. ...
... The action of capsaicin is mediated by TPRV1 (vanilloid receptor), which belongs to an ion channel group. Not only capsaicin but also heat, proton, and Resiniferatoxin (RTX) can activate this receptor leading to many physiological effects (Szallasi &Blumberg, 1999 andNagy et al., 2004). Akiba et al. (2004) reported the discovery of TPRV1 on the beta cells of pancreas and found that capsaicin could activate this receptor resulting in an increase in insulin secretion. ...
This study investigated the effect of different drying methods, such as
solar drying at 45oC and conventional drying at 60oC on the quality of red
chili pepper for two varieties Serrano and Fresno. There were no significant
difference between drying methods effects on chemical composition of the
two varieties Serrano and Fresno with the exception of moisture which
decreased in conventional dried samples more than solar. Meanwhile, the
conventional drying method had the highest capsaicin content extracted by
ethanol (2.74 and 1.28 %) for Serrano and Fresno varieties respectively. The
antioxidant activity of fresh red chili pepper recorded the highest values
(95.32 and 90.67 %). The effect of dried red chili pepper at 1 and 2% and the
pure capsaicin at 0.015% were studied in experiments using male albino rats
containing 20 % high fat diet (HFD) rendered diabetic with alloxan injection
for 4 weeks. The lowest value of blood serum glucose was with G4 that fed
HFD + 0.015% capsaicin that recorded 160 mg/dl. Moreover, serum
cholesterol as well as serum triglycerides for the diabetic groups G4 and also
G6 “fed HFD + 2% Serrano red dried chili pepper” were significantly low.
The HDL concentration for the groups G4 and G6 were significantly higher
than the G3 diabetic rats fed with HFD. Feeding the groups of diabetic rats
with HFD + 1 or 2% dried red chili pepper or 0.015% capsaicin, the LDL and
VLDL levels as well as total lipids were significantly low as compared with
control diabetic HFD “G3”. The histopathological examination of liver and
pancreas show that G4 and G6 of diabetic rats fed HFD, either administerated
with 0.015 % capsaicin or fed with diet containing 2% dried Serrano pepper
had the best histological examination for liver or pancreas. The chemical
composition of all prepared chicken patty samples were almost the same,
meanwhile, the chicken patty samples containing 2 % Serrano pepper show
the best results for all physical and microbiological examination as well as
sensory evaluation.
Keywords: Red chili, Capsicum annum, capsaicin, drying, type 2 diabetes,
cholesterol, high fat diet, chicken patties
... Most of the studies showing the beneficial effects of TRPV activation are based on studies showing the neuroprotective effects of capsaicin, since capsaicin possesses a dual role of TRPV activation (transient) followed by prolonged desensitization of TRPV channels [73][74][75]. Therefore, the mechanisms involved in producing neuroprotection may depend on the dose and duration of capsaicin treatment. ...
Transient receptor potential vanilloid subfamily member 1 (TRPV1) has been strongly implicated in the pathophysiology of cerebral stroke. However, the exact role and mechanism remain elusive. TPRV1 channels are exclusively present in the neurovascular system and involve many neuronal processes. Numerous experimental investigations have demonstrated that TRPV1 channel blockers or the lack of TRPV1 channels may prevent harmful inflammatory responses during ischemia–reperfusion injury, hence conferring neuroprotection. However, TRPV1 agonists such as capsaicin and some other non-specific TRPV1 activators may induce transient/slight degree of TRPV1 channel activation to confer neuroprotection through a variety of mechanisms, including hypothermia induction, improving vascular functions, inducing autophagy, preventing neuronal death, improving memory deficits, and inhibiting inflammation. Another factor in capsaicin-mediated neuroprotection could be the desensitization of TRPV1 channels. Based on the summarized evidence, it may be plausible to suggest that TPRV1 channels have a dual role in ischemia–reperfusion-induced cerebral injury, and thus, both agonists and antagonists may produce neuroprotection depending upon the dose and duration. The current review summarizes the dual function of TRPV1 in ischemia–reperfusion-induced cerebral injury models, explains its mechanism, and predicts the future.
Graphical Abstract
... However, it can be activated through a wide range of stimuli, including contact with nociceptive compounds and noxious heat (Caterina et al., 1997;Tominaga and Julius, 2000;Caterina and Julius, 2001). Moreover, several of such nociceptive compounds are produced and released upon tissue injury and ischemia, including H + , K + , bradykinin, reactive oxygen species, and prostaglandins (Nagy et al., 2004;Randhawa and Jaggi, 2015). TRPV1 activation results in Na + and Ca 2+ influx, inducing neuronal depolarization and the local release of neuropeptides, such as calcitonin gene-related peptide (CGRP) and substance P (Holzer, 1988;Maggi and Meli, 1988). ...
The meticulous control of cardiac sympathetic and parasympathetic tone regulates all facets of cardiac function. This precise calibration of cardiac efferent innervation is dependent on sensory information that is relayed from the heart to the central nervous system. The vagus nerve, which contains vagal cardiac afferent fibers, carries sensory information to the brainstem. Vagal afferent signaling has been predominantly shown to increase parasympathetic efferent response and vagal tone. However, cardiac vagal afferent signaling appears to change after cardiac injury, though much remains unknown. Even though subsequent cardiac autonomic imbalance is characterized by sympathoexcitation and parasympathetic dysfunction, it remains unclear if, and to what extent, vagal afferent dysfunction is involved in the development of vagal withdrawal. This review aims to summarize the current understanding of cardiac vagal afferent signaling under in health and in the setting of cardiovascular disease, especially after myocardial infarction, and to highlight the knowledge gaps that remain to be addressed.
... In the early 19th century, researchers pointed out that capsaicin, the main pungent component in "hot" chili pepper, caused a burning sensation and pain in mammalian mucosa or skin (Nagy et al., 2004). In 1997, Caterina et al. successfully cloned and isolated the first capsaicin-sensitive receptor from rat dorsal root ganglion and named it vanilloid receptor subtype 1 (VR1) (Caterina et al., 1997). ...
TRPV1 is a non-selective channel receptor widely expressed in skin tissues, including keratinocytes, peripheral sensory nerve fibers and immune cells. It is activated by a variety of exogenous or endogenous inflammatory mediators, triggering neuropeptide release and neurogenic inflammatory response. Previous studies have shown that TRPV1 is closely related to the occurrence and/or development of skin aging and various chronic inflammatory skin diseases, such as psoriasis, atopic dermatitis, rosacea, herpes zoster, allergic contact dermatitis and prurigo nodularis. This review summarizes the structure of the TRPV1 channel and discusses the expression of TRPV1 in the skin as well as its role of TRPV1 in skin aging and inflammatory skin diseases.
... The obtained pregnancy rates in synchronized buffaloes might be linked to CPS supplementation in the experimental animals. One aspect of CPS supplementation and enhanced fertility is explained that it binds to receptors in the plasma membrane and activate ligand-gated, nonselective cation channels for the excitation of sensory neurons [22,23] and CPS-excited sensory neurons, which in turn improve granulosa cells proliferation [24], folliculogenesis and fertility in different species [11,25,26]. Increased metabolism and availability of nutrients, particularly glucose, at breeding and during the initial stages of pregnancy by CPS supplementation might be an involved mechanism for the enhancement of fertility in buffaloes during the low breeding season. ...
The present study investigated the role of dietary capsaicin (CPS) supplementation on milk yield (liters/head) and milk composition (total solids, lactose, albumin, protein, fat, milk urea nitrogen (MUN), somatic cell count (SCC) and somatic cell score (SCS), serum metabolites (lipoprotein esterase (LPL) and aspartate aminotransferase (AST)), and reproductive physiology (follicular development, estrus response, ovulation and pregnancy) following synchronization during the low breeding season. One hundred (n = 100) crossbred buffaloes were randomly assigned to four dietary groups consisting of CPS supplementation dosages (0, 2, 4 or 6 mg/kg of total mixed ration; TMR) as CPS-0 (n = 26), CPS-2 (n = 22), CPS-4 (n = 25) and CPS-6 (n = 27), respectively, in a 30-day feed trial. The results revealed that the CPS-4 group of buffaloes had a better estrus rate (72%) along with improved (p < 0.05) ovulatory follicle diameter (13.8 mm), ovulation rate (68%) and pregnancy rate (48%) compared to other treatment groups. Milk yield improved (p < 0.05) in CPS-4 supplemented buffaloes after day 20 of the trial, comparatively. There was a significant effect (p < 0.05) of milk sampling day (day 30) on total milk solids, lactose, milk protein and MUN levels, whereas lactose, MUN, SCC and SCS were influenced by supplementation dosage (CPS-4). Glucose levels were affected in buffaloes by sampling time (artificial insemination (AI) and 50-day post-AI) and CPS-dose (CPS-4 and CPS-6), respectively. LPL level changed in CPS-2 and CPS-4 groups at AI time and 50 days after AI. In addition, the AST level was different in CPS-4 at AI time and 50 days after AI. Therefore, our data suggest that a medium dose (~4 mg/kg of TMR) of CPS provided a better response in the form of milk yield, milk composition, serum metabolites and reproductive performance in crossbred buffaloes during the low breeding season.
... In another interesting study, eugenol and its analogs were reported to interact with vanilloid receptors in the olfactory bulb and displayed a positive effect on memory [122]. Such a possibility can be explored for the treatment of AD and PD. ...
Ficus religiosa (Bo tree or sacred fig) and Ficus benghalensis (Indian banyan) are of immense spiritual and therapeutic importance. Various parts of these trees have been investigated for their antioxidant, antimicrobial, anticonvulsant, antidiabetic, anti-inflammatory, analgesic, hepatopro-tective, dermoprotective, and nephroprotective properties. Previous reviews of Ficus mostly discussed traditional usages, photochemistry, and pharmacological activities, though comprehensive reviews of the neuroprotective potential of these Ficus species extracts and/or their important phy-tocompounds are lacking. The interesting phytocompounds from these trees include many ben-galenosides, carotenoids, flavonoids (leucopelargonidin-3-O-β-d-glucopyranoside, leucopelargo-nidin-3-O-α-l-rhamnopyranoside, lupeol, cetyl behenate, and α-amyrin acetate), flavonols
... TRPV1 est fortement exprimé au niveau des fibres Aδ et C mais on le retrouve aussi au niveau des kératinocytes de la peau (Nagy et al., 2004). Il a été démontré qu'il est impliqué dans la transduction de stimuli nociceptifs thermiques (> 43 °C) et mécaniques ; par ailleurs, il jouerait aussi un rôle dans les processus inflammatoires (Danigo et al., 2013). ...
La neuropathie périphérique diabétique, complication majeure du diabète de type 2, augmente le risque de complications sévères comme les ulcères et l’amputation. La dysfonction microvasculaire présente chez les sujets diabétiques peut expliquer à elle seule le développement de la neuropathie. Les mécanismes de contrôle de la microcirculation (endothéliaux, neurogénique, myogénique, respiratoire et cardiaque) peuvent être appréhendés par l’analyse spectrale des oscillations du flux sanguin : le flowmotion. Cette thèse a tout d’abord défini une nouvelle recommandation du temps d’enregistrement minimal de signaux obtenus par Laser Doppler Flowmeter nécessaire pour faire une analyse fiable de ce flowmotion. Les modifications du flowmotion peuvent précéder l'apparition des indices globaux de complications microangiopathiques chez le DT2. Aussi nous avons ensuite exploré les changements microcirculatoires et du flowmotion lors d’un stress hémodynamique (récupération post-exercice) et lors d’un stimulus vasoconstricteur (déclivité du pied) sur un large spectre de patients : des sujets obèses aux patients diabétiques de type 2 sans neuropathie à ceux avec des stades de sévérité de neuropathie différents. Nous avons ainsi démontré la dégradation des réponses microcirculatoires, à un stade avancé de la neuropathie, basée sur une altération des contributions endothéliale et neurogénique et une suractivation neurogénique à un stade infraclinique. Enfin, l’étude de l’application de champs magnétiques comme thérapie alternative dans la prise en charge de la douleur neuropathique est actuellement en cours. Au final, ces travaux de thèse ont permis une meilleure compréhension des mécanismes de l’atteinte microcirculatoire du patient diabétique de type 2 avec ou sans neuropathie.
... Capsaicin was able to activate TRPV1 based on previous literatures. [39] The capability of activating TRPV1 of U373 cells for CSPN was then studied. As Ca 2+ would influx into cells if TRPV1 was activated, a Ca 2+ fluorescence probe Fluo-8 was used to detect intracellular Ca 2+ for indirectly proving the activation of TRPV1. ...
Calcium‐overload cancer therapy has gained more and more attention owing to its good therapeutic efficacy with low side effect. However, conventional calcium‐overload therapy is achieved by introducing an additional calcium element into the tumor site by nanomedicines, which may also lead to the calcium‐overload of normal organs, causing an undesirable side effect. To address such issues, capsaicin‐decorated semiconducting polymer nanoparticles (CSPN) are designed to modulate the calcium ion channel of cancer cells for calcium‐overload cancer therapy without adding an additional calcium element. CSPN is composed of a near‐infrared (NIR) absorbing semiconducting polymer (SP) PCPDTBT and a capsaicin‐conjugated amphiphilic copolymer, PEG‐PHEMA‐Cap. Under NIR laser irradiation, PCPDTBT can generate singlet oxygen (¹O2), which not only triggers the release of capsaicin, but also induces photodynamic therapy (PDT). The released capsaicin can further activate transient receptor potential cation channel subfamily V member 1 (TRPV1) of U373 cancer cells, leading to an influx of calcium ions into cells. In addition, the intense NIR‐II fluorescence signal of CSPN makes it suitable for tumor imaging. Thus, this study develops a tumor specific nanotheranostic system for NIR‐II fluorescence imaging‐guided calcium‐overload/PDT combination therapy.
... The mechanism of action for capsaicin includes inactivation of an ion channel in cutaneous nerve fibers called transient release potential vanilloid-1 (TRPV1). 15 Activation of TRPV1 stimulates neurons to release and eventually deplete certain neuropeptides, including substance P. Through its effects on nociceptive nerve endings, capsaicin induces a long-lasting desensitization of neurons to a variety of stimuli leading to inhibition of neuronal transmission of pain and pruritus. Recent findings indicate that TRPV1 is expressed in many areas of the central nervous system including the spinal cord, layers 3 and 5 of the cerebral cortex, reticular formation, locus coeruleus, numerous subcortical structures, cerebellar cortex, hypothalamus, substantia nigra and more. ...
Objectives
To report a case associating the use of Oleoresin Capsicum Pepper Spray (OCPS) during law enforcement training with development of Reversible Cerebral Vasoconstriction Syndrome (RCVS).
Materials and Methods
RCVS is radiographically characterized by multifocal smooth narrowing of cerebral arteries heralded by clinical manifestations of recurrent thunderclap headaches. 70% of cases with RCVS have a clear precipitating factor and agents commonly implicated were cannabis, selective serotonin reuptake inhibitors, nasal decongestants, cocaine, postpartum state, eclampsia and strenuous physical/sexual activity.¹
Results
24-year-old female police officer with no past medical history who presented with thunderclap headaches after exposure to pepper spray to her face during work training. Neurological examination was unremarkable. CT angiogram (CTA) of the head and neck and subsequent conventional angiogram revealed multifocal mild arterial narrowing of bilateral middle cerebral arteries (MCA), bilateral posterior cerebral arteries (PCA) and left anterior cerebral artery (ACA) concerning for RCVS. Eight weeks later, she had a repeat MRA head and neck demonstrating complete resolution of the previously noted narrowing of her cerebral arteries.
Conclusions
OCPS is widely used in law enforcement training as well as by general population as a self- defense tool. It is generally assumed to be safe, although the consequences of its use can never be predicted with certainty.² As our case highlights, use of OCPS may be associated with development of RCVS and awareness needs to be raised regarding this rare but serious complication.
... Biochemical pharmacology of vanilloid receptors: [5][6][7][8][9][10][11][12][13][14][15][16] Molecular structure: It consists of 6 membrane domains with a short pore forming region between the fifth and sixth domains. It comprises of long amino terminus with about 400amino acid residues containing 3 ankyrin domains and a Vanilloid receptors in health and disease: [17] I. Pain and inflammation: [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] a) TRPV1 and inflammation: TRPV1 nonselective cation channel highly expressed on sensory neurons can be a promising target for treatment of acute and chronic pain states. ...
... It is known that the TRPV1 receptor is built up of four identical subunits, each of which is formed by six transmembrane domains, S1-S6 [1,18]. Both N-and C-terminals of each subunit are located at the cytoplasmic side of the membrane. ...
The work was carried out on primary cultures of neurons (1- to 2-day-long cultivation) isolated from DRGs of 8- to 12-day-old rats; fluorescent microscopy was used for evaluation of the level of intracellular calcium in the studied units. Small-sized neurons supposedly attributable to nociceptors (diameter 21–37 μm and mean surface area 589 ± 96 μm2) were selected. Capsaicin (100 nM) was applied for 5–10 sec with 2- to 3-min-long intervals. After 30–40 min, this protocol was continued by application of 100 μM uridine-5’-triphosphate for 1–2 min; then capsaicin was applied again. All DRG neurons demonstrating calcium responses to capsaicin could be divided into four groups, units with slow-enhancing capsaicin effects demonstrating desensitization (n = 30; 49%), those with rapidly developing capsaicin effects followed by desensitization (n = 12; 20%), neurons with rapid capsaicin responses and no desensitization (n = 11; 18%), and units with slow responses with no desensitization (n = 8; 13%). Applications of uridine-5’-triphosphate (UTP) to capsaicin-affected neurons with desensitization caused full or partial resensitization of TRPV1 receptors.
... TRPV1-selective agonists, such as capsaicin, produce transient channel activation and Ca 2+ influx followed by desensitization with analgesic effects [42,43]. However, the clinical application of TRPV1 agonists is limited because of the pain and the neurotoxic side effects correlated with the channel activity [44,45]. ...
Arthritis is a widespread inflammatory disease associated with progressive articular surface degradation, ongoing pain, and hyperalgesia causing the development of functional limitations and disability. TRPV1 channel is one of the high-potential targets for the treatment of inflammatory diseases. Polypeptide APHC3 from sea anemone Heteractis crispa is a mode-selective TRPV1 antagonist that causes mild hypothermia and shows significant anti-inflammatory and analgesic activity in different models of pain. We evaluated the anti-inflammatory properties of APHC3 in models of monosodium iodoacetate (MIA)-induced osteoarthritis and complete Freund’s adjuvant (CFA)-induced rheumatoid monoarthritis in comparison with commonly used non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac, ibuprofen, and meloxicam. Subcutaneous administration of APHC3 (0.1 mg/kg) significantly reversed joint swelling, disability, grip strength impairment, and thermal and mechanical hypersensitivity. The effect of APHC3 was equal to or better than that of reference NSAIDs. Protracted treatment with APHC3 decreased IL-1b concentration in synovial fluid, reduced inflammatory changes in joints, and prevented the progression of cartilage degradation. Therefore, polypeptide APHC3 has the potential to be an analgesic and anti-inflammatory substance for the alleviation of arthritis symptoms.
... TRPV1 channels are located in intracellular and mitochondrial membranes as well [17,18]. TRPV1 is activated and/or sensitized by several stimuli produced upon hypoxia, tissue injury and inflammation including noxious heat (> 43 • C) and chemical stimuli like H + or K + , bradykinin, reactive oxygen species (ROS), and prostaglandins [19,20]. Activation of TRPV1 induces Na + and Ca 2+ influx as well as consequent membrane depolarization and the local release of several neuropeptides such as calcitonin gene-related peptide (CGRP), substance P (SP), and pituitary adenylate cyclase-activating polypeptide (PACAP) (Figure 1). ...
Cardiovascular diseases, including coronary artery disease, ischemic heart diseases such as acute myocardial infarction and postischemic heart failure, heart failure of other etiologies, and cardiac arrhythmias, belong to the leading causes of death. Activation of capsaicin-sensitive sensory nerves by the transient receptor potential vanilloid 1 (TRPV1) capsaicin receptor and other receptors, as well as neuropeptide mediators released from them upon stimulation, play important physiological regulatory roles. Capsaicin-sensitive sensory nerves also contribute to the development and progression of some cardiac diseases, as well as to mechanisms of endogenous stress adaptation leading to cardioprotection. In this review, we summarize the role of capsaicin-sensitive afferents and the TRPV1 ion channel in physiological and pathophysiological functions of the heart based mainly on experimental results and show their diagnostic or therapeutic potentials. Although the actions of several other channels or receptors expressed on cardiac sensory afferents and the effects of TRPV1 channel activation on different non-neural cell types in the heart are not precisely known, most data suggest that stimulation of the TRPV1-expressing sensory nerves or stimulation/overexpression of TRPV1 channels have beneficial effects in cardiac diseases.
... Capsaicin is shown to stimulate different TRPV channels that enhance calcium influx resulting a migratory phenotype [14,35]. TRPV1 is the mostoften mentioned protein targets of capsaicin that belongs to a member of the TRP family of non-selective cation channels [36]. Interestingly, in null-TRPV1 urothelial cancer cells, capsaicin promotes more aggressive gene phenotypes and invasiveness, which is totally opposite to its impact in TRPV1-overexpressing cells [37], supporting the contradictory role of capsaicin on cell motility. ...
We have studied the chemopreventive property of capsaicin, a major active component in chili pepper, and found that it exhibited apoptotic activity against various lines of cancer cells. Interestingly, accumulating data has revealed that, in addition to cytotoxicity, capsaicin also plays regulatory role on cell migration and invasion. However, its effect on cell migration is paradoxical and not completely understood. Here, we set out to elucidate the molecular events underlying capsaicin-inhibited cell migration in bladder cancer cells. Our results show that the cap-saicin-reduced cell migration was associated with down-regulation of sirtuin 1 (SIRT1) deacetylase, possibly through proteasome-mediated protein degradation. More importantly, we employed a cellular thermal shift assay (CETSA) to demonstrate that there was a direct binding between capsaicin and SIRT1. The engagement with capsaicin and protein degradation diminished the deacetylase of SIRT1, which in turn, enhanced acetylation of cortactin and β-catenin to decrease MMP-2 and MMP-9 activation, resulting in cell migration impairment in bladder cancer cells.
... Due to its potential as a specific toxin for peripheral C-fiber, capsaicin has been used extensively as a versatile tool in the study of pain mechanisms [10,12,25,26]. TRPV1 is expressed in a substantial proportion of C-fiber neurons, and its activation by capsaicin affects the function of C-fiber [27,28]. Parental administration of capsaicin to neonatal rats resulted in the permanent destruction of small B type sensory ganglion cells and of 80-95% of afferent C-fiber in the lumbar dorsal roots [24,29]. ...
Capsaicin is the active component of chili peppers and is a hydrophobic, colorless, odorless, and crystalline to waxy compound. The transient receptor potential vanilloid 1 (TRPV1) is the capsaicin receptor channels that are involved in a variety of functions like transduction and transmission of the physiological stimulus. Subcutaneous injection of capsaicin to a newborn rat leads to involuntary lifelong TRPV1 desensitization. Various physiological changes including sensory and homeostatic actions in the body associated with neonatal capsaicin treatment are induced by direct TRPV1 channel targeting. Interesting changes include unique phenomena such as the reduction in pain perception, abnormal body temperature, increase in infection, infectious or neuropathological itching, and irregular circadian core body temperature rhythm. These symptoms are associated with relatively higher fever or loss of sensory c-fiber related to TRPV1 desensitization. The aforementioned outcomes not only provide a warning about the risk of capsaicin exposure in newborns but also indicate the possible occurrence of relatively rare diseases that are difficult to diagnose. Therefore, Therefore, the present review aims to summarize the unique phenomena caused by systemic capsaicin administration in neonatal rats.
... Besides, CAP is currently being utilized for therapeutic treatment of various clinical conditions such as pain relief, rheumatoid arthritis, diabetic neuropathy, obesity, cardiovascular and gastrointestinal conditions (Josse et al., 2010;Sharma et al., 2013). CAP excites sensory neurons by binding to its receptor (TRPV1-capsaicin-sensitive receptor transient receptor potential, vanilloid type 1), localize on primary afferent neurons (Wardle et al., 1997;Nagy et al., 2004;Nakagawa and Hiura 2006). CAP-sensitive sensory neurons are nociceptive neurons that are known to activate ligand-gated, nonselective cation channels such as CGRP, substance P (SP) and neurokinin A (Jessell et al., 1978;Saria et al., 1987). ...
Capsaicin (trans-8-methyl-N-vanillyl-6-noneadamide) is a pungent ingredient in red peppers from the Capsicum family. Insulin-like growth factor-I (IGF-I) is expressed in granulosa cells and has an important role in ovarian development. However, there are no data about the IGF-I expression in ovarian granulosa cells after capsaicin treatment. The aim of this study was to investigate the expression of IGF-I and its receptor (insulin-like growth factor-I receptor [IGF-IR]) in primary rat ovarian granulosa cells after low and high doses of capsaicin treatment. For this, granulosa cells were isolated and cultured from ovaries of 30-day-old female Sprague-Dawley rats. Granulosa cell plates were divided into four groups as cell control (C), vehicle control (V), and 50 μM and 150 μM capsaicin groups. In experimental groups, granulosa cells were exposed to capsaicin for 24 hours and immunocytochemistry was performed afterwards using anti-IGF-I and anti-IGF-IR antibodies. Both IGF-I and IGF-IR expressions were found to be significantly increased in parallel to the capsaicin doses. Elevated levels of IGF-I may be a risk factor for ovarian development. Because of the crucial role of IGF-I in ovary development, capsaicin treatment can be effective on follicular development and/or disorders characterized by high IGF-I levels.
... The TRPV1 receptor is generally regarded as a molecular integrator of nociceptive stimuli and can be activated by noxious heat (~43 • C), acidic pH, and exogenous (capsaicin) and endogenous vanilloids (e.g., anandamide) [41][42][43][44]. Furthermore, it has been revealed that various agents released upon tissue damage and inflammation, such histamine, prostaglandin E2, bradykinin and nerve growth factor (NGF) sensitize the TRPV1 receptor [44][45][46][47]. Capsaicin-sensitive PSNs contain different neuropeptides, such as substance P (SP), calcitonin gene-related peptide (CGRP) and somatostatin [48][49][50]. ...
Insulin, besides its pivotal role in energy metabolism, may also modulate neuronal processes through acting on insulin receptors (InsRs) expressed by neurons of both the central and the peripheral nervous system. Recently, the distribution and functional significance of InsRs localized on a subset of multifunctional primary sensory neurons (PSNs) have been revealed. Systematic investigations into the cellular electrophysiology, neurochemistry and morphological traits of InsR-expressing PSNs indicated complex functional interactions among specific ion channels, proteins and neuropeptides localized in these neurons. Quantitative immunohistochemical studies have revealed disparate localization of the InsRs in somatic and visceral PSNs with a dominance of InsR-positive neurons innervating visceral organs. These findings suggested that visceral spinal PSNs involved in nociceptive and inflammatory processes are more prone to the modulatory effects of insulin than somatic PSNs. Co-localization of the InsR and transient receptor potential vanilloid 1 (TRPV1) receptor with vasoactive neuropeptides calcitonin gene-related peptide and substance P bears of crucial importance in the pathogenesis of inflammatory pathologies affecting visceral organs, such as the pancreas and the urinary bladder. Recent studies have also revealed significant novel aspects of the neurotrophic propensities of insulin with respect to axonal growth, development and regeneration.
... There is ample evidence that the effects of capsaicin are being mediated through the activation of the transient receptor potential vanilloid type 1 receptor (TRPV1) also known as the vanilloid receptor 1 or the capsaicin receptor (Caterina et al., 1997) expressed in chemosensitive primary sensory neurons. TRPV1 receptor physiologically can be activated and/or sensitized by several stimuli, such as H + , K + , bradykinin, ROS and prostaglandins (Nagy, Santha, Jancso, & Urban, 2004;Randhawa & Jaggi, 2015; Figures 1 and 2). Another TRP receptor, transient receptor potential ankyrin 1 (TRPA1) is expressed and co-localized with TRPV1 receptors in the cardiac muscle (Andrei, Sinharoy, Bratz, & Damron, 2016). ...
During the last decades, mortality from acute myocardial infarction has been dramatically reduced. However, the incidence of post‐infarction heart failure is still increasing. Cardioprotection by ischaemic conditioning had been discovered more than three decades ago. Its clinical translation, however, is still an unmet need. This is mainly due to the disrupted cardioprotective signalling pathways in the presence of different cardiovascular risk factors, co‐morbidities and the medication being taken. Sensory neuropathy is one of the co‐morbidities that has been shown to interfere with cardioprotection. In the present review, we summarize the diverse aetiology of sensory neuropathies and the mechanisms by which these neuropathies may interfere with ischaemic heart disease and cardioprotective signalling. Finally, we suggest future therapeutic options targeting both ischaemic heart and sensory neuropathy simultaneously.
LINKED ARTICLES
This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc
... TRPV1 is a molecular integrator of different nociceptor stimuli including noxious heat, acidic pH, and capsaicin. It is significantly involved in the mediation of heat hyperalgesia and inflammatory pain, too [53][54][55][56][57]. TRPV1 is the archetypal nociceptive ion channel and is expressed by practically all nociceptive primary sensory neurons which, in the rat, are mostly polymodal nociceptors [58,59]. ...
Gangliosides are abundantly occurring sialylated glycosphingolipids serving diverse functions in the nervous system. Membrane-localized gangliosides are important components of lipid microdomains (rafts) which determine the distribution of and the interaction among specific membrane proteins. Different classes of gangliosides are expressed in nociceptive primary sensory neurons involved in the transmission of nerve impulses evoked by noxious mechanical, thermal, and chemical stimuli. Gangliosides, in particular GM1, have been shown to participate in the regulation of the function of ion channels, such as transient receptor potential vanilloid type 1 (TRPV1), a molecular integrator of noxious stimuli of distinct nature. Gangliosides may influence nociceptive functions through their association with lipid rafts participating in the organization of functional assemblies of specific nociceptive ion channels with neurotrophins, membrane receptors, and intracellular signaling pathways. Genetic and experimentally induced alterations in the expression and/or metabolism of distinct ganglioside species are involved in pathologies associated with nerve injuries, neuropathic, and inflammatory pain in both men and animals. Genetic and/or pharmacological manipulation of neuronal ganglioside expression, metabolism, and action may offer a novel approach to understanding and management of pain.
... The TRPV1 receptor is a non-selective cation channel predominantly expressed in sensory neurons with the nerve fibers innervating the heart and blood vessels [24]. Previous studies have suggested that cardiac TRPV1 may be activated by chemical mediators produced during ischemia and reperfusion, including protons, adenosine, and bradykinin. ...
Myocardium ischemia-reperfusion injury (IRI) is the major cause of postoperative cardiac dysfunction. While intrathecal morphine preconditioning (ITMP) can reduce IRI in animals, the molecular processes underlying IRI and ITMP remain elusive. Transient receptor potential vanilloid type 1 (TRPV1)is highly expressed in cardiac sensory neurons and has a crucial role in detecting myocardial ischemia. This study aimed to determine the role of up-regulated dorsal root ganglion (DRG)-TRPV1 in IRI and whether its inhibition contributes to ITMP-induced cardioprotection. Animal model of IRI was established by left coronary artery occlusion (30 min) and reperfusion (2 h) in rats. Intrathecal intubation was prepared for morphine preconditioning, TRPV1-shRNA or selective TRPV1 antagonist administration. After IRI, both protein and phosphorylation levels of TRPV1 were significantly increased, and the immunofluorescence intensity of TRPV1 was increased and colocalized with μ-opioid receptors in DRG. Intrathecal pre-administration of either TRPV1-shRNA or TRPV1 antagonist significantly reduced myocardial injury and the upregulation of TRPV1 in DRG induced by IRI. Simultaneously, ITMP significantly suppressed TRPV1 protein expression and phosphorylation in DRG, as well as the heart infarct size and arrhythmia score caused by IRI. The suppression of TRPV1 elevation and activation by ITMP were reversed by intrathecal injection of the selective μ receptor antagonist. Furthermore, IRI elevated DRG cAMP, while intrathecal administration of the selective cAMP-PKA inhibitor reduced myocardial injury. Finally, we showed that activation of opioid receptor by morphine inhibited PKA activator-induced TRPV1 channel activity at the cellular level. These findings suggest that the elevation and activation of TRPV1 in DRG during myocardial ischemia-reperfusion might be responsible for cardiac injury. ITMP exerts cardioprotection by inhibiting DRG-TRPV1 activity via modulation cAMP. Therefore, inhibition of TRPV1 upregulation in DRG might be used as a novel therapeutic mechanism for myocardium ischemia-reperfusion injury.
... TRP receptor channels of the vanilloid type 1 (TRPV1) have been intensely studied for more than two decades in the spinal and the trigeminal system (Nagy, Sántha, Jancsó, & Urbán, 2004). They are essential for heat transduction expressed in most of the slowly conducting nociceptive afferents (Dux, Sántha, & Jancsó, 2012;Julius, 2013;Numazaki & Tominaga, 2004). ...
Background:
The α1 -adrenoceptor agonist, phenylephrine, is used at high concentrations as a mydriatic agent and for the treatment of nasal congestion. Among its adverse side effects transient burning sensations are reported indicating activation of the trigeminal nociceptive system.
Methods:
Neuropeptide release, calcium imaging and meningeal blood flow recordings were applied in rodent models of meningeal nociception to clarify possible receptor mechanisms underlying these pain phenomena.
Results:
Phenylephrine above 10 mM dose-dependently released calcitonin gene-related peptide (CGRP) from the dura mater and isolated trigeminal ganglia, while hyperosmotic mannitol at 90 mM was ineffective. The phenylephrine-evoked release was blocked by the transient receptor potential vanilloid 1 (TRPV1) antagonist BCTC and did not occur in trigeminal ganglia of TRPV1-deficient mice. Phenylephrine at 30 mM caused calcium transients in cultured trigeminal ganglion neurons responding to the TRPV1 agonist capsaicin and in HEK293T cells expressing human TRPV1. Local application of phenylephrine at micromolar concentrations to the exposed rat dura mater reduced meningeal blood flow, whereas concentrations above 10 mM caused increased meningeal blood flow. The flow increase was abolished by pre-application of the CGRP receptor antagonist CGRP8-37 or the TRPV1 antagonist BCTC.
Conclusions:
Phenylephrine at high millimolar concentrations activates TRPV1 receptor channels of perivascular afferents and, upon calcium inflow, releases CGRP, which increases meningeal blood flow. Activation of TRPV1 receptors may underlie trigeminal nociception leading to cranial pain such as local burning sensations or headaches caused by administration of high doses of phenylephrine.
... The transient receptor potential vanilloid 1 (TRPV1), a member of the vanilloid TRP family, is a non-selective cation channel identified as the capsaicin receptor [11]. It is involved in pain evoked and activated by a plethora of stimuli, including heat, voltage, vanilloids, lipids, protons, and cations [12]. ...
The landscape of cellular plasticity and sources with relevant niche signals in hepatocellular carcinoma is still obscure. Transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel, is involved in a variety of malignancies and overexpressed in hepatocellular carcinoma (HCC). We have investigated the role of TRPV1 in HCC from different angles by various experimental techniques, such as in vivo and in vitro experiments, and by bioinformatics analysis of data from genetic models induced by diethylnitrosamine (DEN), mice samples and human HCC samples. We find that TRPV1 knockout promotes to hepatocarcinogenesis and deconstructs the portal triad adjacent to tumor border that is contributed by originations of tumor initiating cells and biliary cells. Epithelial to mesenchymal transition (EMT) is involved and transcription factors Ovol2 and Zeb1 coordinated with Sox 10 drive gene expression in the event which is also confirmed by the expression of these proteins in human HCC samples. Treatment with TRPV1 agonist Capsaicin inhibits the growth of HCC cells in xenograft models. Our findings demonstrate that TRPV1 is a potential therapeutic target in human HCC and exerts effects on cellular plasticity with modulation of Ovol2, Zeb1 and Sox10.
... Capsaicin is shown to stimulate different TRPV channels that enhance calcium influx resulting a migratory phenotype [14,35]. TRPV1 is the mostoften mentioned protein targets of capsaicin that belongs to a member of the TRP family of non-selective cation channels [36]. Interestingly, in null-TRPV1 urothelial cancer cells, capsaicin promotes more aggressive gene phenotypes and invasiveness, which is totally opposite to its impact in TRPV1-overexpressing cells [37], supporting the contradictory role of capsaicin on cell motility. ...
We have studied the chemopreventive property of capsaicin, a major active component in chili pepper, and found that it exhibited apoptotic activity against various lines of cancer cells. Interestingly, accumulating data has revealed that, in addition to cytotoxicity, capsaicin also plays regulatory role on cell migration and invasion. However, its effect on cell migration is paradoxical and not completely understood. Here, we set out to elucidate the molecular events underlying capsaicin-inhibited cell migration in bladder cancer cells. Our results show that the capsaicin-reduced cell migration was associated with down-regulation of sirtuin 1 (SIRT1) deacetylase, possibly through proteasome-mediated protein degradation. More importantly, we employed a cellular thermal shift assay (CETSA) to demonstrate that there was a direct binding between capsaicin and SIRT1. The engagement with capsaicin and protein degradation diminished the deacetylase of SIRT1, which in turn, enhanced acetylation of cortactin and β-catenin to decrease MMP-2 and MMP-9 activation, resulting in cell migration impairment in bladder cancer cells.
... TRPV1 is a non-discriminating calcium channel engaged in nociceptive circuits in the peripheral nervous system (PNS) and synaptic plasticity in the central nervous system (CNS). TRPV1 has been detected in the nervous system, including in dorsal root ganglia, trigeminal ganglia, striatum, hypothalamus, cerebellum, and primary sensory neurons [25,53,56,72]. Experimental rat studies showed that TRPV1 is exogenously induced by capsaicin [7,8,75]. ...
Abstract Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Objectives This study aimed to examine the role of capsaicin dietary exposure in ameliorating cognitive functions in experimental rat model of streptozotocin-induced Alzheimer’s disease (STZ-induced AD). Methods Thirty adult albino male rats were distributed randomly into three equal groups. Ten rats, served as negative controls, were treated once with intracerebroventricular (icv) injection and intragastric infusion of saline for 47 days. Twenty rats were treated with a single icv-STZ (3 mg/kg) injection for induction of AD. Behavioral tests were done after 2 weeks to evaluate the development of Alzheimer’s model. Rats with retention latency less than 300 s in the passive avoidance test were further subdivided into 2 groups; one group was treated with intragastric infusion of capsaicin (10 mg/kg) for 47 days and the other group was treated similarly with saline as positive controls. Then, behavioral tests were repeated at the end of the experiment. The expression level of β-amyloid 1-42 peptide (Aβ1-42) and tau proteins was measured using ELISA test. Results The behavioral impairments had been ameliorated by capsaicin treatment. Furthermore, there was improvement in the estimated biochemical parameters as revealed by the significant decline in the mean values of β-amyloid 1-42 peptide (Aβ1-42) and tau proteins in hippocampal homogenate in capsaicin-treated group as compared to the positive controls (p
... Systemic administration of appropriate dose of capsaicin, a highly selective sensory neurotoxin, leads to a selective dysfunction of a morphologically well-defined group of primary sensory nerves [6][7][8]. Therefore, sensory desensitization induced by systemic capsaicin treatment is a well-accepted model to investigate the pathology and pharmacology of sensory neuropathy, see [9,10] for reviews. Cardiac sensory nerves play a pivotal role in myocardial adaptation processes to ischemic injury including ischemic pre-, post-, and remote conditioning [11][12][13]. ...
Background:
Here we examined myocardial microRNA (miRNA) expression profile in a sensory neuropathy model with cardiac diastolic dysfunction and aimed to identify key mRNA molecular targets of the differentially expressed miRNAs that may contribute to cardiac dysfunction.
Methods:
Male Wistar rats were treated with vehicle or capsaicin for 3 days to induce systemic sensory neuropathy. Seven days later, diastolic dysfunction was detected by echocardiography, and miRNAs were isolated from the whole ventricles.
Results:
Out of 711 known miRNAs measured by miRNA microarray, the expression of 257 miRNAs was detected in the heart. As compared to vehicle-treated hearts, miR-344b, miR-466b, miR-98, let-7a, miR-1, miR-206, and miR-34b were downregulated, while miR-181a was upregulated as validated also by quantitative real time polymerase chain reaction (qRT-PCR). By an in silico network analysis, we identified common mRNA targets (insulin-like growth factor 1 (IGF-1), solute carrier family 2 facilitated glucose transporter member 12 (SLC2a-12), eukaryotic translation initiation factor 4e (EIF-4e), and Unc-51 like autophagy activating kinase 2 (ULK-2)) targeted by at least three altered miRNAs. Predicted upregulation of these mRNA targets were validated by qRT-PCR.
Conclusion:
This is the first demonstration that sensory neuropathy affects cardiac miRNA expression network targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2, which may contribute to cardiac diastolic dysfunction. These results further support the need for unbiased omics approach followed by in silico prediction and validation of molecular targets to reveal novel pathomechanisms.
... Previous studies demonstrated that a unique population of C-fiber DRG neurons is sensitive to capsaicin and express the transient receptor potential vanilloid type 1 receptor (TRPV1) (Jancsó et al., 1977;Buck and Burks, 1986;Holzer, 1991;Caterina et al., 1997;Guo et al., 2001). These neurons are involved in pain sensation and, in a variety of organs, local regulatory functions, including neurogenic inflammation brought about by the release of sensory neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) (Jancsó, 1960;Jancso et al., 1968, Jancsó et al., 1977Maggi and Meli, 1988;Holzer, 1991;Nagy et al., 2004). These TRPV1-immunoreactive (IR) nociceptive DRG neurons comprise two major subpopulations: CGRP-containing peptidergic and Bandeiraea simplicifolia isolectin B4 (IB4)binding non-peptidergic neurons (Silos-Santiago et al., 1995;Santha et al., 2010). ...
Apart from its pivotal role in the regulation of carbohydrate metabolism, insulin exerts important neurotrophic and neuromodulator effects on dorsal root ganglion (DRG) neurons. The neurite outgrowth-promoting effect is one of the salient features of insulin’s action on cultured DRG neurons. Although it has been established that a significant population of DRG neurons express the insulin receptor (InsR), the significance of InsR expression and the chemical phenotype of DRG neurons in relation to the neurite outgrowth-promoting effect of insulin has not been studied. Therefore, in this study by using immunohistochemical and quantitative stereological methods we evaluated the effect of insulin on neurite outgrowth of DRG neurons of different chemical phenotypes which express or lack the InsR. Insulin, at a concentration of 10 nM, significantly increased total neurite length, the length of the longest neurite and the number of branch points of cultured DRG neurons as compared to neurons cultured in control medium or in the presence of 1 μM insulin. In both the control and the insulin exposed cultures, ∼43% of neurons displayed InsR-immunoreactivity. The proportions of transient receptor potential vanilloid type 1 receptor (TRPV1)-immunoreactive (IR), calcitonin gene-related peptide (CGRP)-IR and Bandeiraea simplicifolia isolectin B4 (IB4)-binding neurons amounted to ∼61%, ∼57%, and ∼31% of DRG neurons IR for the InsR. Of the IB4-positive population only neurons expressing the InsR were responsive to insulin. In contrast, TRPV1-IR nociceptive and CGRP-IR peptidergic neurons showed increased tendency for neurite outgrowth which was further enhanced by insulin. However, the responsiveness of DRG neurons expressing the InsR was superior to populations of DRG neurons which lack this receptor. The findings also revealed that besides the expression of the InsR, inherent properties of peptidergic, but not non-peptidergic nociceptive neurons may also significantly contribute to the mechanisms of neurite outgrowth of DRG neurons. These observations suggest distinct regenerative propensity for differing populations of DRG neurons which is significantly affected through insulin receptor signaling.
... In this study, we found that the promotional effect of NaHS on gastric acid secretion could be attenuated by capsazepine (a TRPV1 antagonist) and L703606 (a NK 1 receptor antagonist). These results suggest that the excitatory effect of NaHS on gastric acid secretion might be mediated by activation of TRPV1 channels in sensory nerve terminals, with the consequent release of substance P. TRPV1 is broadly expressed in all 'port of entry' tissues, such as the skin, gut, airway and conjunctiva (28)(29), and which is abundantly expressed in primary afferent nerve endings (30). Capsaicin, the agonist of TRPV1 receptors, excites intestinal motility by activating the local efferent function of sensory nerves, this effect might be mediated by tachykinins (most likely SP) released from afferent nerves (31). ...
Hydrogen sulfide (H2S) promotes gastric acid secretion in rats. The present study aimed to test the hypothesis that H2S regulates this response via activating TRPV1 channel and through activation of the nuclear factor-κB (NF-κB) pathway. Male Wistar rats were randomly divided into the sodium hydrosulfide (NaHS, 100 μmol/kg b.w.) group, pyrrolidine dithiocarbamate (PDTC, 100 μmol/kg b.w.) group, PDTC (100 μmol/kg b.w.) + NaHS (100 μmol /kg b.w.) group, capsazepine (0.1 mM) + NaHS (100 μmol /kg b.w.) group and L703606 (0.1 mM) + NaHS (100 μmol /kg b.w.) group. The acidity of gastric juice before injection and after injection were determined by a pH meter. The results showed that sodium hydrosulfide (NaHS), an exogenous H2S donor, significantly reduced the pH of gastric juice when injected into the enterocoelia. Further, the promotional effect of NaHS on gastric acid secretion could be attenuated by capsazepine, a transient receptor potential vanilloid 1 (TRPV1) antagonist; L703606, a neurokinin 1 (NK1) receptor antagonist; and PDTC, a NF-κB inhibitor. The data from these experiments suggest that NaHS exerts an excitatory effect on gastric acid secretion possibly mediated by TRPV1 channel activation in sensory nerve terminals with the consequent release of substance P and in a NF-κB -dependent manner.
... Finally, the possibility should also be considered that the TRPV1-like immunoreactive fibres in the LK belong, at least in part, to descending projections. In fact, experimental evidence underlines the role of supraspinal TRPV1 in pain modulation, the rostral-ventrolateral medulla (RVM), periaqueductal grey (PAG), amygdala, solitary tract nucleus, locus coeruleus, somatosensory and anterior cingulated cortex, and insula being the territories most involved in this functional meaning [15,[136][137][138][139][140][141][142]. Although the knowledge of the TRPV1 role in most of these systems is still incomplete, the TRPV1-mediated activation of the PAG-RVM antinociceptive pain pathway has drawn attention as a possible pharmacological target for some types of intractable pain [142]. ...
The presence of transient receptor potential vanilloid type-1 receptor (TRPV1)-like immunoreactivity (LI), in the form of nerve fibres and terminals, is shown in a set of discrete gray matter subregions placed in the territory of the human cuneate nucleus. We showed previously that those subregions share neurochemical and structural features with the protopathic nuclei and, after the ancient name of our town, collectively call them Locus Karalis, and briefly Locus K. TRPV1-LI in the Locus K is codistributed, though not perfectly overlapped, with that of the neuropeptides calcitonin gene-related peptide and substance P, the topography of the elements immunoreactive to the three markers, in relation to each other, reflecting that previously described in the caudal spinal trigeminal nucleus. Myelin stainings show that myelinated fibres, abundant in the cuneate, gracile and trigeminal magnocellular nuclei, are scarce in the Locus K as in the trigeminal substantia gelatinosa. Morphometric analysis shows that cell size and density of Locus K neurons are consistent with those of the trigeminal substantia gelatinosa and significantly different from those of the magnocellular trigeminal, solitary and dorsal column nuclei. We propose that Locus K is a special component of the human dorsal column nuclei. Its functional role remains to be determined, but TRPV1 appears to play a part in it.
Hot peppers, also called chilli, chilli pepper, or paprika of the plant genus Capsicum (family Solanaceae), are one of the most used vegetables and spices worldwide. Capsaicin (8-methyl N-vanillyl-6-noneamide) is the main pungent principle of hot green and red peppers. By acting on the capsaicin receptor or transient receptor potential cation channel vanilloid subfamily member 1 (TRPV1), capsaicin selectively stimulates and in high doses defunctionalizes capsaicin-sensitive chemonociceptors with C and Aδ afferent fibers. This channel, which is involved in a wide range of neuronal processes, is expressed in peripheral and central branches of capsaicin-sensitive nociceptive neurons, sensory ganglia, the spinal cord, and different brain regions in neuronal cell bodies, dendrites, astrocytes, and pericytes. Several experimental and clinical studies provided evidence that capsaicin protected against ischaemic or excitotoxic cerebral neuronal injury and may lower the risk of cerebral stroke. By preventing neuronal death, memory impairment and inhibiting the amyloidogenic process, capsaicin may also be beneficial in neurodegenerative disorders such as Parkinson’s or Alzheimer’s diseases. Capsaicin given in systemic inflammation/sepsis exerted beneficial antioxidant and anti-inflammatory effects while defunctionalization of capsaicin-sensitive vagal afferents has been demonstrated to increase brain oxidative stress. Capsaicin may act in the periphery via the vagal sensory fibers expressing TRPV1 receptors to reduce immune oxidative and inflammatory signalling to the brain. Capsaicin given in small doses has also been reported to inhibit the experimentally-induced epileptic seizures. The aim of this review is to provide a concise account on the most recent findings related to this topic. We attempted to delineate such mechanisms by which capsaicin exerts its neuronal protective effects. We also aimed to provide the reader with the current knowledge on the mechanism of action of capsaicin on sensory receptors.
We describe an in silico-guided rational drug design and the synthesis of the suggested ligands, aimed at improving the TRPV1-ligand binding properties and the potency of N-(4-hydroxy-3-methoxybenzyl)-4-(thiophen-2-yl) butanamide I, a previously identified TRPV1 agonist. The docking experiments followed by molecular dynamics simulations and thermodynamic analysis led the drug design toward both the introduction of a lipophilic iodine and a flat pyridine/benzene at position 5 of the thiophene nucleus. Most of the synthesized compounds showed high TRPV1 efficacy and potency as well as selectivity. The molecular modeling analysis highlighted crucial hydrophobic interactions between Leu547 and the iodo-thiophene nucleus, as in amide 2a, or between Phe543 and the pyridinyl moiety, as in 3a. In the biological evaluation, both compounds showed protective properties against oxidative stress-induced ROS formation in human keratinocytes. Additionally, while 2a showed neuroprotective effects in both neurons and rat brain slices, 3a exhibited potent antinociceptive effect in vivo..
Bladder afferents play a crucial role in urine storage and voiding, and conscious sensations from the bladder. Endocannabinoids, anandamide (AEA) and 2-arachidonolylglycerol (2-AG), are endogenous ligands of G-protein coupled cannabinoid receptors 1 and 2 (CB1 and CB2) found in the CNS and peripheral organs. They also have off-target effects on some ligand- and voltage-gated channels. The aim of this study is to determine the role of AEA and 2-AG in regulation of mechanosensitivity of probable nociceptive neurons innervating the bladder - capsaicin-sensitive mucosal afferents. The activity of these afferents was determined by ex vivo single unit extracellular recordings in the guinea pig bladder. A stable analogue of anandamide, methanandamide (mAEA) evoked initial excitatory response of mucosal afferents followed by potentiation of their responses to mechanical stimulation. In the presence of TRPV1 antagonist (AMG9810), mAEA's effect on mechanosensitivity switched from excitatory to inhibitory. The inhibitory effect of mAEA is due to activation of both CB1 and CB2 cannabinoid receptors since it was abolished by combined application of selective CB1 (NESS0327) and CB2 (SR144528) antagonists. 2-AG application evoked a brief excitation of mucosal afferents, without potentiation of their mechanosensitivity, followed by the inhibition of their responses to mechanical stimulation. CB2 receptor antagonist, SR144528 abolished the inhibitory effect of 2-AG. Our data indicated that anandamide and 2-AG have opposite effects on mechanosensitivity of mucosal capsaicin-sensitive afferents in the guinea pig bladder; mAEA potentiated while 2-AG inhibited responses of mucosal afferents to mechanical stimulation. These findings are important for understanding of the role of endocannabinoids in regulating bladder sensation and function.
Transient receptor potential vanilloid 1 (TRPV1) channel plays an important role in a wide range of physiological and pathological processes, and a comprehensive understanding of TRPV1 gating will create opportunities for therapeutic intervention. Recent incredible advances in cryo-electron microscopy (cryo-EM) have yielded high-resolution structures of all TRPV subtypes (TRPV1–6) and all of them share highly conserved six transmembrane (TM) domains (S1–S6). As revealed by the open structures of TRPV1 in the presence of a bound vanilloid agonist (capsaicin or resiniferatoxin), TM helices S1 to S4 form a bundle that remains quiescent during channel activation, highlighting differences in the gating mechanism of TRPV1 and voltage-gated ion channels. Here, however, we argue that the structural dynamics rather than quiescence of S1–S4 domains is necessary for capsaicin-mediated activation of TRPV1. Using fluorescent unnatural amino acid (flUAA) incorporation and voltage-clamp fluorometry (VCF) analysis, we directly observed allostery of the S1–S4 bundle upon capsaicin binding. Covalent occupation of VCF-identified sites, single-channel recording, cell apoptosis analysis, and exploration of the role of PSFL828, a novel non-vanilloid agonist we identified, have collectively confirmed the essential role of this coordinated S1–S4 motility in capsaicin-mediated activation of TRPV1. This study concludes that, in contrast to cryo-EM structural studies, vanilloid agonists are also required for S1–S4 movement during TRPV1 activation. Redefining the gating process of vanilloid agonists and the discovery of new non-vanilloid agonists will allow the evaluation of new strategies aimed at the development of TRPV1 modulators.
Capsaicin is an alkaloid molecule with outstanding biological activity. Several reports have shown that capsaicin exerts significant antitumoral effects in several cancer cell lines, including gliomas. However, its application has been very limited due to its hydrophobicity, low affinity, and short life span. Gliomas are a heterogeneous group of brain malignant tumors with increasing prevalence worldwide. Standard therapy against these tumors generally includes resection by surgery, radiation, and chemotherapy or their combination. However, elicitation of tumor resistance to chemical or radiation treatments remains one of the main challenges to be resolved, particularly in the case of glioblastomas. Nanotechnology is an innovative approach to the treatment of Central Nervous System diseases and especially to gliomas treatment. Indeed, the use of nanotherapeutic formulations offers several advantages over the conventional methods of drug delivery therapy. In this review, we analyzed the current literature regarding the development of capsaicin-loaded nanoparticles as a promising approach for the treatment of malignant brain tumors.
Ethnopharmacological relevance
ShexiangZhuifeng Analgesic Plaster (SZAP) is a traditional Chinese medicine and transdermal formulation composed of many Chinese herbs and active compounds. SZAP was recently approved by the China Food and Drug Administration for the treatment of pain associated with osteoarticular diseases and is preferred by most rheumatoid arthritis patients in China. However, its mechanism has not been elucidated in detail.
Aim of the study
We sought to determine the analgesic effect of SZAP in collagen-induced arthritis (CIA) rats and explore the underlying mechanisms of pain transmission, such as via the TRPV1 and P2X3 receptors.
Methods
After CIA was established, rats were treated with SZAP for 7 days. Paw thickness, arthritis score, and haematoxylin and eosin staining were used to evaluate the effectiveness of SZAP. Paw withdrawal threshold (PWT) and tail-flick latency (TFL) were used to estimate the analgesic effect of SZAP. The levels of PGE2, BK, 5-HT, SP, and CGRP in the serum and synovium were determined using ELISA kits, and ATP in the synovium was measured using HPLC. The expression of TRPV1 and P2X3 in the DRG was detected using western blotting and immunofluorescence. TRPV1 and P2X3 agonists were further used to determine the analgesic effects of SZAP on CIA rats based on PWT and TFL.
Results
SZAP not only significantly ameliorated arthritis scores and paw thickness by improving the pathological damage of synovial joints, but also remarkably alleviated pain in CIA rats. Further, treatment with SZAP significantly reduced peripheral 5-HT, PGE2 BK, SP, CGRP, and ATP. Additionally, the expression of TRPV1 and P2X3 in the DRG was markedly downregulated by SZAP. Interestingly, the analgesic effect of SZAP was weakened (reduction of PWT and TFL) when TRPV1 and P2X3 were activated by capsaicin or α,β-meATP, respectively.
Conclusion
SZAP ameliorates rheumatalgia by suppressing hyperalgesia and pain transmission through the inhibition of TRPV1 and P2X3 in the DRG of CIA rats.
The present study was conducted to evaluate the effects of dietary addition of capsaicin (CAP) on egg production performance, follicular development, and ovarian antioxidant capacity in laying ducks. Three hundred seventy eight 58-wk-old laying ducks were randomly divided into 3 treatments, each treatment consisted 6 replicates, with 12 individually caged laying ducks per replicate. Ducks fed a basal diet served as control, the other 2 groups of ducks were fed the same diet containing 150 mg/kg CAP but in the manner of feed restriction (pair-fed) or ad libitum fed. The experiment lasted for 8 wk. The results showed that the dietary supplementation with CAP under conditions of ad libitum feeding increased feed intake (P
Tropaeolum tuberosum, commonly known as Mashua, is an herbal remedy used in traditional Andean medicine for the relief of kidney and bladder pain, as well as contusions. This study aimed to evaluate the fractions and isolated compounds from T. tuberosum with analgesic activity mediated by the transient receptor potential vanilloid-1 receptor. A bioguided phytochemical analysis based on NMR/MS was performed to identify the compounds of the n-heptane fractions from samples of purple tubers of T. tuberosum. The transient receptor potential vanilloid-1 agonist and antagonist activity were assessed through the measurement of intracellular Ca2+ in HEK001 cells. The chemical structure determination led to the identification of two alkamides: N-(2-hydroxyethyl)-7Z,10Z,13Z,16Z-docosatetraenamide (1) and N-oleoyldopamine (2). Both compounds induced increased intracellular calcium flow with IC50 values of 3.2 nM and 7.9 nM, respectively, thus activating the transient receptor potential vanilloid-1 receptor. Our research is the first report to show that these two compounds isolated from T. tuberosum can act as agonists of the transient receptor potential vanilloid-1 receptor, providing scientific evidence for the traditional use of this species in pain relief.
Previous studies have demonstrated that nicotine can induce relaxation of the middle cerebral artery (MCA). However, whether this relaxation is associated with the activity of sensory calcitonin gene-related peptide (CGRP) nerves, and whether this is modulated by H facilitating the release of CGRP from sensory CGRPergic nerve terminals in the MCA remains unclear. In this study, we examined the role of H in the modulation of neurogenic vasomotor responses in rat-isolated endothelium-denuded MCA. Wire-myography was used to measure vasoreactivity, and indicated that nicotine-induced relaxation was sensitive to tetrodotoxin and lidocaine, and drastically reduced levels of guanethidine (an adrenergic neuronal blocker), N-nitro-L-arginine (L-NNA), CGRP8-37, vasoactive intestinal polypeptide (VIP)6-28, capsaicin, capsazepine (a transient receptor potential vanilloid-1 inhibitor) and tetraethylammonium. However, this nicotine-induced relaxation was not sensitive to propranolol. Lowering the pH of buffer solution with HCl caused pH-dependent vasorelaxation and deceased intracellular pH in the MCA rings, which was sensitive to L-NNA, CGRP8-37, VIP6-28, capsazepine, 4-aminopyridine (a voltage-gated potassium channel antagonist), and paxilline (a large conductance Ca-activated K channels antagonist). However, HCl-induced relaxation was not inhibited by glibenclamide (an ATP-sensitive K channel blocker). These results suggested that electrical and chemical activation of cerebral perivascular adrenergic nerves led to the release H which then facilitated the release of NO, VIP and CGRP, resulting in vasorelaxation. Lowering the pH of buffer solution caused potassium channels of vascular smooth muscle cells and perivascular nerves to open. In conclusion, our results demonstrated that H may act as a modulator on MCA perivascular nerves and/or smooth muscles.
Purpose
Chilli pepper (Capsicum annum), an extensively cultivated vegetable, is commonly used to spice many dishes prepared in several parts of the world. It contains capsaicinoids. The most active amongst these capsaicinoids is capsaicin (8-methyl-N-vanillyl-6-nonenamide), which is neurogenic and so may affect nervous function. Therefore, the purpose of this paper is to investigate the effects of long-term consumption of chilli pepper and capsaicin diets on pain and social behaviour in CD-1 Swiss white mice.
Design/methodology/approach
In total, 30 male mice were randomly assigned into three groups of ten mice each, namely, control, pepper-diet (20 per cent w/w) and capsaicin-diet (10 per cent w/w) groups. Tail immersion, hot plate and formalin tests were conducted to assess pain perception, while nesting behaviour test was used to evaluate the social behaviour of the mice.
Findings
The latency of tail flick of both the pepper and capsaicin groups were significantly longer (p < 0.01 and p < 0.001, respectively) compared to control. The hind paw lick frequency, duration and flinching of both the pepper and capsaicin groups were also significantly reduced compared to control. The nesting score of the capsaicin group was significantly higher (p < 0.01) compared to control. However, the nesting score for pepper group was significantly lower (p < 0.05) compared to capsaicin group.
Originality/value
Long-term consumption of capsaicin and pepper diets suppressed pain and enhanced organized social behaviour in mice. One of the active principles responsible for the effects obtained with pepper on pain and social behaviour in mice may be capsaicin.
Meissner corpuscles (MCs) in the glabrous skin of monkey digits have at least three types of innervation as revealed by immunofluorescence. The previously well known Aalphabeta-fiber terminals are closely intertwined with endings from peptidergic C-fibers. These intertwined endings are segregated into zones that alternate with zones containing a third type of ending supplied by nonpeptidergic C-fibers. Although MCs are widely regarded as low-threshold mechanoreceptors, all three types of innervation express immunochemical properties associated with nociception. The peptidergic C-fiber endings have readily detectable levels of immunoreactivity (IR) for calcitonin gene-related peptide (CGRP) and substance P (SP). The Aalphabeta endings have relatively lower levels of IR for CGRP and SP as well as the SP neurokinin 1 receptor and vanilloid-like receptor 1. Both the Aalphabeta and peptidergic C-fiber endings were also labeled with antibodies for different combinations of adrenergic, opioid, and purinergic receptors. The nonpeptidergic C-fiber endings express IR for vanilloid receptor 1, which has also been implicated in nociception. Thus, MCs are multiafferented receptor organs that may have nociceptive capabilities in addition to being low-threshold mechanoreceptors.
Capsaicin or vanilloid receptors (VRs) participate in the sensation of thermal and inflammatory pain. The cloned (VR1) and native VRs are non-selective cation channels directly activated by harmful heat, extracellular protons and vanilloid compounds. However, considerable attention has been focused on identifying other signalling pathways in VR activation; it is known that VR1 is also expressed in non-sensory tissue and may mediate inflammatory rather than acute thermal pain. Here we show that activation of protein kinase C (PKC) induces VR1 channel activity at room temperature in the absence of any other agonist. We also observed this effect in native VRs from sensory neurons, and phorbol esters induced a vanilloid-sensitive Ca2+ rise in these cells. Moreover, the pro-inflammatory peptide, bradykinin, and the putative endogenous ligand, anandamide, respectively induced and enhanced VR activity, in a PKC-dependent manner. These results suggest that PKC may link a range of stimuli to the activation of VRs.
The cloned vanilloid receptor VR1 has attracted recent attention as a molecular integrator of painful stimuli on primary sensory
neurons. The existence of vanilloid-sensitive neurons in the brain is, however, controversial. In this study, we have used
an antibody and a complementary RNA probe to explore the distribution of neurons that express VR1 in rat and in certain areas
of human brain. In the rat, we observed VR1-expressing neurons throughout the whole neuroaxis, including all cortical areas
(in layers 3 and 5), several members of the limbic system (e.g., hippocampus, central amygdala, and both medial and lateral
habenula), striatum, hypothalamus, centromedian and paraventricular thalamic nuclei, substantia nigra, reticular formation,
locus coeruleus, cerebellum, and inferior olive. VR1-immunopositive cells also were found in the third and fifth layers of
human parietal cortex. Reverse transcription–PCR performed with rat VR1-specific primers verified the expression of VR1 mRNA
in cortex, hippocampus, and hypothalamus. In the central nervous system, neonatal capsaicin treatment depleted VR1 mRNA from
the spinal nucleus of the trigeminal nerve, but not from other areas such as the inferior olive. The finding that VR1 is expressed
not only in primary sensory neurons but also in several brain nuclei is of great importance in that it places VRs in a much
broader perspective than pain perception. VRs in the brain (and putative endogenous vanilloids) may be involved in the control
of emotions, learning, and satiety, just to name a few exciting possibilities.
The vanilloid receptor-1 (VR1) is a heat-gated ion channel that is responsible for the burning sensation elicited by capsaicin. A similar sensation is reported by patients with esophagitis when they consume alcoholic beverages or are administered alcohol by injection as a medical treatment. We report here that ethanol activates primary sensory neurons, resulting in neuropeptide release or plasma extravasation in the esophagus, spinal cord or skin. Sensory neurons from trigeminal or dorsal root ganglia as well as VR1-expressing HEK293 cells responded to ethanol in a concentration-dependent and capsazepine-sensitive fashion. Ethanol potentiated the response of VR1 to capsaicin, protons and heat and lowered the threshold for heat activation of VR1 from 42°C to 34°C. This provides a likely mechanistic explanation for the ethanol-induced sensory responses that occur at body temperature and for the sensitivity of inflamed tissues to ethanol, such as might be found in esophagitis, neuralgia or wounds.
Tissue injury generates endogenous factors that heighten our sense of pain by increasing the response of sensory nerve endings to noxious stimuli. Bradykinin and nerve growth factor (NGF) are two such pro-algesic agents that activate G-protein-coupled (BK2) and tyrosine kinase (TrkA) receptors, respectively, to stimulate phospholipase C (PLC) signalling pathways in primary afferent neurons. How these actions produce sensitization to physical or chemical stimuli has not been elucidated at the molecular level. Here, we show that bradykinin-or NGF-mediated potentiation of thermal sensitivity in vivo requires expression of VR1, a heat-activated ion channel on sensory neurons. Diminution of plasma membrane phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) levels through antibody sequestration or PLC-mediated hydrolysis mimics the potentiating effects of bradykinin or NGF at the cellular level. Moreover, recruitment of PLC-γ to TrkA is essential for NGF-mediated potentiation of channel activity, and biochemical studies suggest that VR1 associates with this complex. These studies delineate a biochemical mechanism through which bradykinin and NGF produce hypersensitivity and might explain how the activation of PLC signalling systems regulates other members of the TRP channel family.
Arachidonylethanolamide, an arachidonic acid derivative in porcine brain, was identified in a screen for endogenous ligands
for the cannabinoid receptor. The structure of this compound, which has been named "anandamide," was determined by mass spectrometry
and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. Anandamide inhibited the specific binding of a
radiolabeled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands and produced a concentration-dependent
inhibition of the electrically evoked twitch response to the mouse vas deferens, a characteristic effect of psychotropic cannabinoids.
These properties suggest that anandamide may function as a natural ligand for the cannabinoid receptor.
Terminals in the rat spinal cord that express the vanilloid receptor VR1 are from small and medium dorsal root ganglion (DRG) neurons and appear prominent in lamina I and inner lamina II. Because primary afferents from these neurons can be myelinated or unmyelinated and their terminals in these laminae can be of various morphological and functional types, we undertook this study to identify the type(s) of VR1-positive afferent fibers and terminals. In the DRG, many small and medium-sized neurons are immunopositive. Under electron microscopy, dorsal root afferents that are immunopositive for VR1 are predominantly unmyelinated. Large numbers of VR1-positive terminals in lamina I are of the nonglomerular type and may contain dense core vesicles. VR1 immunoreactivity in terminals in lamina I is in good agreement with data on noxious, heat-sensitive neurons in the dorsal horn. Two types of glomerular afferent terminals in lamina II also are immunopositive for VR1. In both laminae, most VR1-positive terminals are distinct from substance P-positive terminals. However, the immunoreactivity in lamina II also is prominent in dendrites that are contacted by primary afferent endings. Because we also observed patchy immunostaining in cell bodies in lamina II, this unexpected result may reflect synthesis of VR1 by neurons in this lamina. However, because dorsal rhizotomy abolishes VR1 staining in both laminae I and II, it is suggested that the expression and intracellular dynamics of VR1 in lamina II neurons are controlled by presynaptic input. J. Comp. Neurol. 436:225-235, 2001. (C) 2001 Wiley -Liss, Inc.
The functions of the lower urinary tract, to store and periodically release urine, are dependent on the activity of smooth and striated muscles in the urinary bladder, urethra, and external urethral sphincter. This activity is in turn controlled by neural circuits in the brain, spinal cord, and peripheral ganglia. Various neurotransmitters, including acetylcholine, norepinephrine, dopamine, serotonin, excitatory and inhibitory amino acids, adenosine triphosphate, nitric oxide, and neuropeptides, have been implicated in the neural regulation of the lower urinary tract. Injuries or diseases of the nervous system, as well as drugs and disorders of the peripheral organs, can produce voiding dysfunctions such as urinary frequency, urgency, and incontinence or inefficient voiding and urinary retention. This chapter will review recent advances in our understanding of the pathophysiology of voiding disorders and the targets for drug therapy.
Abstract The ε-isozyme of protein kinase C (PKCε) and the vanilloid receptor 1 (VR1) are both expressed in dorsal root ganglion (DRG) neurons and are reported to be predominantly and specifically involved in nociceptive function. Using phosphospecific antibody against the C-terminal hydrophobic site Ser729 of PKCε as a marker of enzyme activation, the state-dependent activation of PKCε, as well as the expression of VR1 in rat DRG neurons, was evaluated in different experimental pain models in vivo. Quantitative analysis showed that phosphorylation of PKCε in DRG neurons was significantly up-regulated after carrageen- and Complete Freund's Adjuvant-induced inflammation, while it was markedly down-regulated after chronic constriction injury. A double-labeling study showed that phosphorylation of PKCε was expressed predominantly in VR1 immunoreactivity positive small diameter DRG neurons mediating the nociceptive information from peripheral tissue to spinal cord. The VR1 protein expression showed no significant changes after either inflammation or chronic constriction injury. These data indicate that functional activation of PKCε has a close relationship with the production of inflammatory hyperalgesia and the sensitization of the nociceptors. Inflammatory mediator-induced activation of PKCε and subsequent sensitization of VR1 to noxious stimuli by PKCε may be involved in nociceptor sensitization.
Substance P, acting via the neurokinin 1 receptor (NK1R), plays an important role in mediating a variety of inflammatory processes.
However, its role in acute pancreatitis has not been previously described. We have found that, in normal mice, substance P
levels in the pancreas and pancreatic acinar cell expression of NK1R are both increased during secretagogue-induced experimental
pancreatitis. To evaluate the role of substance P, pancreatitis was induced in mice that genetically lack NK1R by administration
of 12 hourly injections of a supramaximally stimulating dose of the secretagogue caerulein. During pancreatitis, the magnitude
of hyperamylasemia, hyperlipasemia, neutrophil sequestration in the pancreas, and pancreatic acinar cell necrosis were significantly
reduced in NK1R−/− mice when compared with wild-type NK1R+/+ animals. Similarly, pancreatitis-associated lung injury, as characterized
by intrapulmonary sequestration of neutrophils and increased pulmonary microvascular permeability, was reduced in NK1R−/−
animals. These effects of NK1R deletion indicate that substance P, acting via NK1R, plays an important proinflammatory role
in regulating the severity of acute pancreatitis and pancreatitis-associated lung injury.
Capsaicin, the active ingredient in hot peppers, produces a long-lasting reduction of nociceptive reactions in rodents through a selective toxic action on afferent C-fibres. Immediate effects on C-fibre conduction are also found in other mammalian species and a reduction in nociceptive responses from human skin occurs following topical application. Direct application to nerve trunks may be expected to produce a useful degree of regional analgesia in man. Since this effect would occur without any anaesthesia or paralysis, it appears worth investigating as a treatment for pain of peripheral origin in man.
(C) Lippincott-Raven Publishers.
The responses of rabbit urinary bladder to hydrostatic pressure changes and to electrical stimulation have been investigated using both the Ussing chamber and a superfusion apparatus. These experiments enabled us to monitor changes in both ionic transport across the tissue and cellular ATP release from it.
The urinary bladder of the rabbit maintains an electrical potential difference across its wall as a result largely of active sodium transport from the urinary (mucosal) to the serosal surface.
Small hydrostatic pressure differences produced by removal of bathing fluid from one side of the tissue caused reproducible changes in both potential difference and short‐circuit current. The magnitude of these changes increases as the volume of fluid removed increases.
Amiloride on the mucosal (urinary), but not the serosal, surface of the membrane reduces the transepithelial potential difference and short‐circuit current with an IC 50 of 300 n m . Amiloride reduces the size of, but does not abolish, transepithelial potential changes caused by alterations in hydrostatic pressure.
Field electrical stimulation of strips of bladder tissue produces a reproducible release of ATP. Such release was demonstrated to occur largely from urothelial cells and is apparently non‐vesicular as it increases in the absence of calcium and is not abolished by tetrodotoxin.
It is proposed that ATP is released from the urothelium as a sensory mediator for the degree of distension of the rabbit urinary bladder and other sensory modalities.
• Excitation and sensitization to heat of nociceptors by bradykinin (BK) were examined using an isolated rat skin-saphenous nerve preparation. • A total of 52 C-fibres was tested: 42 were mechano-heat sensitive (CMH) and 40 % of them were excited and sensitized to heat by BK superfusion (10−5m, 5 min) of their receptive fields; heat responses were augmented by more than five times and heat thresholds dropped to 36.4 °C, on average. • Sixty per cent of the CMH did not respond to BK itself, but 3/4 of these units showed an increase in their heat responses by more than 100 % following BK exposure. • Ten high-threshold mechanosensitive C-fibres did not discharge upon BK application but following this five of them responded to heat in a well-graded manner. • In all fibres, the sensitizing effect of BK was abolished within 9 min or less of wash-out, and it could be reproduced several times at equal magnitude, whereas the excitatory effect of BK regularly showed profound tachyphylaxis. • Sustained superfusion (20 min) of BK induced a desensitizing excitatory response while superimposed heat responses showed constant degrees of sensitization. • The large extent and high prevalence of BK-induced sensitization (almost 80 % of all fibres tested) and de novo recruitment of heat sensitivity suggest a prominent role of BK not only in hyperalgesia but also in sustained inflammatory pain which may be driven by body or even lower local temperatures acting on sensitized nociceptors. • Based on the latter assumption, a hypothesis is put forward that excludes a direct excitatory effect of BK on nociceptors, but assumes a temperature-controlled activation as a result of rapid and profound sensitization.
In the absence of indomethacin, anandamide did not contract the guinea-pig bronchus at concentrations up to 100 μM. In the presence of indomethacin (10 μM), anandamide induced concentration-related contractions with a pEC50 value of 5.18±0.11. It was significantly less potent than capsaicin (pEC50 7.01±0.1). The anandamide uptake inhibitor AM404, produced only a 14.1±3.22% contraction at 100 μM. All experiments were conducted in the presence of PMSF (20 μM).
The vanilloid receptor antagonist, capsazepine (10 μM), significantly attenuated the contractile effect of anandamide, the response to 100 μM anandamide being 40.53±7.04% in the presence of vehicle and 1.57±8.93% in the presence of 10 μM capsazepine. The contractile actions of anandamide and AM404 were markedly enhanced by the peptidase inhibitor thiorphan.
The log concentration-response curve of anandamide was unaltered by the CB1 receptor antagonist, SR141716A. The pEC50 values for anandamide were 4.88±0.08 and 5.17±0.19 in the presence of vehicle and SR141716A (1 μM) respectively.
The lipoxygenase inhibitors 5,8,11,14-eicosatetraynoic acid (ETYA) and 5,8,11 eicosatriynoic acid (ETI) reduced the effect of 100 μM anandamide from 34.7±1.9% (vehicle) to 7.7±5% (ETYA, 10 μM) and from 41.85±4.25% (n=6) (vehicle) to 10.31±3.54 (n=6) (ETI, 20 μM). Neither inhibitor significantly affected contraction of the tissue by substance P.
This study provides evidence that anandamide acts on vanilloid receptors in the guinea-pig isolated bronchus. These data raise the possibility that the contractile action of anandamide may be due, at least in part, to lipoxygenase metabolites of this fatty acid amide that are vanilloid receptor agonists.
British Journal of Pharmacology (2001) 134, 30–37; doi:10.1038/sj.bjp.0704223
Unlabelled:
Among several mediators, nitric oxide (NO) and calcitonin gene-related peptide (CGRP) were suggested to be involved in the mechanism of preconditioning. We examined the possible role of the cardiac capsaicin-sensitive sensory innervation in pacing-induced preconditioning, as well as in the cardiac NO and CGRP content. Wistar rats were treated subcutaneously with capsaicin or its solvent in the sequence of 10, 30, and 50 mg/kg increasing single daily doses for 3 days to deplete neurotransmitters of the sensory innervation. Isolated hearts from both groups were then subjected to either preconditioning induced by three consecutive periods of pacing at 600 beats per minute for 5 min with 5 min interpacing periods, or time-matched non-preconditioning perfusion, followed by a 10-min coronary occlusion. NO content of left ventricular tissue samples was assayed by electron-spin resonance, and CGRP release was determined by radioimmunoassay. CGRP immunohistochemistry was also performed. In the non-preconditioned, solvent-treated group, coronary occlusion decreased cardiac output (CO) from 68.1 to 32.1 mL/min, increased left ventricular end-diastolic pressure (LVEDP) from 0.58 to 1.90 kPa, and resulted in 200 mU/min/g LDH release. Preconditioning significantly increased ischaemic CO to 42.9 mL/min (P < 0.05), decreased ischaemic LVEDP to 1.26 kPa (P < 0.05) and decreased LDH release to 47 mU/min/g (P < 0.05) in the solvent-treated group. Preconditioning did not confer protection in the capsaicin-pretreated group (ischaemic CO: 35.6 mL/min; LVEDP: 1.76 kPa; LDH 156 mU/min/g). Capsaicin-treatment markedly decreased cardiac NO content, CGRP release, and CGRP-immunoreactivity.
Conclusions:
(i) The presence of an intact local sensory innervation is a prerequisite to elicit pacing-induced preconditioning in the rat heart. (ii) A significant portion of cardiac basal NO content may be of neural origin. (iii) Release of NO and CGRP from capsaicin-sensitive nerves may be involved in the mechanism of pacing-induced preconditioning.
An implicit Lagrangian for the dual of a simple reformulation of the standard quadratic program of a linear support vector machine is proposed. This leads to the minimization of an unconstrained differentiable convex function in a space of dimensionality equal to the number of classified points. This problem is solvable by an extremely simple linearly convergent Lagrangian support vector machine (LSVM) algorithm. LSVM requires the inversion at the outset of a single matrix of the order of the much smaller dimensionality of the original input space plus one. The full algorithm is given in this paper in 11 lines of MATLAB code without any special optimization tools such as linear or quadratic programming solvers. This LSVM code can be used "as is" to solve classification problems with millions of points. For example, 2 million points in 10 dimensional input space were classified by a linear surface in 82 minutes on a Pentium III 500 MHz notebook with 384 megabytes of memory (and additional swap space), and in 7 minutes on a 250 MHz UltraSPARC II processor with 2 gigabytes of memory. Other standard classification test problems were also solved. Nonlinear kernel classification can also be solved by LSVM. Although it does not scale up to very large problems, it can handle any positive semidefinite kernel and is guaranteed to converge. A short MATLAB code is also given for nonlinear kernels and tested on a number of problems.
The tachykinin NK1 receptor is widely distributed in both the central and peripheral nervous system. In the CNS, NK1 receptors have been implicated in various behavioural responses and in regulating neuronal survival and degeneration. Moreover, central NK1 receptors regulate cardiovascular and respiratory function and are involved in activating the emetic reflex. At the spinal cord level, NK1 receptors are activated during the synaptic transmission, especially in response to noxious stimuli applied at the receptive field of primary afferent neurons. Both neurophysiological and behavioural evidences support a role of spinal NK1 receptors in pain transmission. Spinal NK1 receptors also modulate autonomic reflexes, including the micturition reflex. In the peripheral nervous system, tachykinin NK1 receptors are widely expressed in the respiratory, genitourinary and gastrointestinal tracts and are also expressed by several types of inflammatory and immune cells. In the cardiovascular system, NK1 receptors mediate endothelium-dependent vasodilation and plasma protein extravasation. At respiratory level, NK1 receptors mediate neurogenic inflammation which is especially evident upon exposure of the airways to irritants. In the carotid body, NK1 receptors mediate the ventilatory response to hypoxia. In the gastrointestinal system, NK1 receptors mediate smooth muscle contraction, regulate water and ion secretion and mediate neuro-neuronal communication. In the genitourinary tract, NK1 receptors are widely distributed in the renal pelvis, ureter, urinary bladder and urethra and mediate smooth muscle contraction and inflammation in response to noxious stimuli. Based on the knowledge of distribution and pathophysiological roles of NK1 receptors, it has been anticipated that NK1 receptor antagonists may have several therapeutic applications at central and peripheral level. At central level, it is speculated that NK1 receptor antagonists could be used to produce analgesia, as antiemetics and for treatment of certain forms of urinary incontinence due to detrusor hyperreflexia. In the peripheral nervous system, tachykinin NK1 receptor antagonists could be used in several inflammatory diseases including arthritis, inflammatory bowel diseases and cystitis. Several potent tachykinin NK1 receptor antagonists are now under evaluation in the clinical setting, and more information on their usefulness in treatment of human diseases will be available in the next few years.
The endogenous cannabinoid receptor agonist anandamide is a powerful vasodilator of isolated vascular preparations, but its mechanism of action is unclear. Here we show that the vasodilator response to anandamide in isolated arteries is capsaicin-sensitive and accompanied by release of calcitonin-gene-related peptide (CGRP). The selective CGRP-receptor antagonist 8-37 CGRP, but not the cannabinoid CB1 receptor blocker SR141716A, inhibited the vasodilator effect of anandamide. Other endogenous (2-arachidonylglycerol, palmitylethanolamide) and synthetic (HU 210, WIN 55,212-2, CP 55,940) CB1 and CB2 receptor agonists could not mimic the action of anandamide. The selective 'vanilloid receptor' antagonist capsazepine inhibited anandamide-induced vasodilation and release of CGRP. In patch-clamp experiments on cells expressing the cloned vanilloid receptor (VR1), anandamide induced a capsazepine-sensitive current in whole cells and isolated membrane patches. Our results indicate that anandamide induces vasodilation by activating vanilloid receptors on perivascular sensory nerves and causing release of CGRP. The vanilloid receptor may thus be another molecular target for endogenous anandamide, besides cannabinoid receptors, in the nervous and cardiovascular systems.
The neurogenic sensory vascular responses of the dura mater encephali are considered to contribute significantly to the mechanisms of meningeal nociception and headache. Although the fundamental role of capsaicin-sensitive afferent nerves in the development of the neurogenic inflammatory responses of a variety of tissues is well established, their participation in meningeal vascular reactions is unclear. In the present study, the effects of the topical application of capsaicin on the dural blood flow and on the morphology of the dural nerve fibres were examined in control and capsaicin-pretreated rats by means of laser Doppler flowmetry and electron microscopy, respectively. In the control rats, the dural application of capsaicin at concentrations of 50 and 100 nm induced significant increases in blood flow in the branches of the medial meningeal artery. This capsaicin-induced vasodilatation was abolished by capsazepine, a transient receptor potential vanilloid 1 (TRPV1) receptor antagonist, and by hCGRP8–37, a calcitonin gene-related peptide (CGRP) receptor antagonist. Administration of capsaicin at higher concentrations (1 and 10 μm) resulted in marked, dose-dependent decreases in dural blood flow. The capsaicin-induced vasodilatation was abolished, whereas vasoconstriction was augmented, by systemic pretreatment of the animals with capsaicin. Electron microscopy revealed degenerating unmyelinated axons in the dura mater after an acute exposure to capsaicin (10 μm), providing support for the existence and possible functional role of capsaicin-sensitive dural afferent nerves. The results indicate that capsaicin-induced vasodilatation in the rat dura mater is mediated by the release of CGRP from the sensory nerves, whereas the vasoconstrictor response may be attributed to a direct action of capsaicin on the vascular smooth muscle. The present study demonstrates for the first time that capsaicin-sensitive nociceptive afferent nerves contribute significantly to the dural vasodilatory responses and suggests an important role in meningeal nociception.
A single intrathecal injection of capsaicin depletes substance P from primary sensory neurons and causes a prolonged increase in the thermal and chemical pain thresholds of the rat but no apparent change in responses to noxious mechanical stimuli.
PHARMACOLOGICALLY evoked selective degeneration of neurones with a specific function or functioning with known transmitter substances, has been reported only in the monoaminergic neurone systems1,2. We report here that selective degeneration of neurones with a highly specific function can be produced by chemical agents in the somatosensory system as well. Capsaicin given to newborn rats induces selective degeneration of a distinct population of primary sensory neurones involved in mediation of chemogenic pain.
Capsaicin treatment of newborn rats results in the degeneration of primary sensory neurones involved in the mediation of chemogenic pain. In the present study glial changes following the pharmacologically-induced degeneration of unmyelinated primary afferent fibres terminating in Rexed's laminae I and II of the spinal cord were investigated. Light microscopy revealed an increase in the number of phagocytic glial cells in this area, reaching a maximum at 24 h after the administration of capsaicin; they had almost completely disappeared by 72 h. At the ultrastructural level these cells were characterized by their elongate or irregular nuclei with a pronounced heterochromatin pattern, a moderately dense cytoplasmic matrix, hour-glass shaped mitochondria and very large numbers of heterogeneous dense bodies and lipid droplets. On the basis of these observations, these cells were considered to represent reactive microglial cells engaged in the phagocytosis of degenerated neuronal debris. The possible origin and mode of elimination of these elements from the central nervous tissue is briefly discussed.
This paper describes a randomized parallel trial of topical 0.075% capsaicin versus vehicle (placebo) in the postmastectomy pain syndrome (PMPS). The study was double-blind in design; however, this was compromised by the burning sensation induced by capsaicin. We could not demonstrate a significant difference in the visual analogue scale (VAS) for steady pain although a trend was present. A significant difference was found, however, in the VAS for jabbing pain, in category pain severity scales, and in overall pain relief scales in favour of capsaicin. Five of 13 patients on capsaicin were categorized as good-to-excellent responses with 8 (62%) having 50% or greater improvement. Only 1 of 10 cases had a good response to vehicle with 3 rated as 50% or better.
Airway epithelial cells carry out their physiologic role in part by activating phospholipase-fatty acid oxygenation pathways. Recent discoveries include the facts that (a) airway epithelial cells contain abundant stores of fatty acid substrates, including arachidonic acid, for oxygenation, (b) the cells release arachidonic acid upon activation of specific phospholipases, (c) the cells contain novel cyclooxygenases and lipoxygenases at high levels relative to other cell types, and (d) some of the arachidonate metabolites have potent biologic effects on airway end organs such as smooth muscle, nerves, mucus glands, and epithelial cells themselves. Studies of arachidonate metabolism in airway epithelial cells have often been done on a heterogeneous cell population of basal, ciliated, and goblet cells, so information on individual cell types and alterations during cellular differentiation is still poorly defined. Potential cell-cell interaction via transcellular synthesis of eicosanoids also requires further study. Each of these aims would be aided by the use of cultured airway epithelial cells, but the culture system has proven problematic in preserving the oxygenation phenotype of the original tissue. The same access of the epithelial cells to inhaled agents will permit lipid-modifying drugs to be delivered to them, and much of this therapeutic potential is still unexplored. Therefore, determining the factors that regulate arachidonic acid metabolism in airway epithelial cells is still a fundamental goal for unraveling the role of arachidonate products in airway function and for altering eicosanoid production in the airway.
Submucosal blood vessels of the mammalian stomach are densely innervated by neurons containing calcitonin gene-related peptide (CGRP), substance P, neurokinin A, and vasoactive intestinal polypeptide (VIP). Because all these peptides are vasodilators in certain vascular beds, we tested the hypothesis that rat alpha-CGRP, rat VIP, substance P, and neurokinin A are candidate mediators of noncholinergic vasodilator neurons in the gastric mucosa and submucosa. The experiments were performed on urethane-anesthetized Sprague-Dawley rats. Gastric mucosal blood flow (GMBF) was measured by the hydrogen gas clearance technique, and the peptides were infused close arterially to the stomach via a catheter inserted retrogradely in the splenic artery. Basal GMBF was in the range of 35-50 ml/min/100 g. Infusion of rat alpha-CGRP (15 and 75 pmol/min) significantly increased GMBF in a dose-dependent manner, whereas mean arterial blood pressure was significantly lowered only by the higher dose of CGRP. Substance P (125 and 625 pmol/min) and neurokinin A (50 and 250 pmol/min) failed to alter GMBF, although the higher dose of each peptide led to a significant decrease in mean arterial blood pressure. Infusion of rat VIP (25 pmol/min) failed to affect GMBF and mean arterial blood pressure, whereas a fivefold higher dose of VIP (125 pmol/min) led to a significant rise of GMBF and to significant hypotension. These findings indicate that substance P and neurokinin A are unlikely to be of physiological significance for the regulation of GMBF. CGRP and VIP, however, can be considered as candidate mediators of submucosal nerve endings involved in the neural control of GMBF.(ABSTRACT TRUNCATED AT 250 WORDS)
The aim of the study was to assess which type(s) of tachykinin receptor mediate the noncholinergic bronchoconstriction produced by activation (electrical field stimulation) of capsaicin-sensitive primary afferents in epithellum-denuded guinea-pig isolated bronchi. Experiments with natural and synthetic tachykinin agonists indicated the presence of both NK-1 and NK-2 receptors at this level. Experiments with the putative NK-1 (L668, 169) or NK-2 (MEN 10,207, MEN 10,376, L659,877, and R396) selective antagonists against NK-1 and NK-2 selective agonists further supported this conclusion. All the tachykinin antagonists tested reduced the noncholinergic bronchoconstriction to field stimulation with the order of potency MEN 10,207 = MEN 10,376 greater than L659,877 greater than L668,169 congruent to R396. In the presence of peptidase inhibitors, the activity of MEN 10,376 toward the noncholinergic bronchoconstriction was slightly reduced, whereas that of L668,169 was increased. These findings demonstrate that both NK-1 and NK-2 receptors mediate the noncholinergic constriction produced by endogenous tachykinins in guinea-pig bronchi and that the relative contribution of NK-2 receptors is greater than that of NK-1. These findings implicate a major role for neurokinin A rather than for substance P as an endogenous bronchoconstrictor in the guinea-pig isolated bronchi. In the presence of peptidase inhibitors, the relative contribution of NK-1 receptors is increased.
We conducted an 8-wk controlled study with topical 0.075% capsaicin in subjects with chronic severe painful diabetic neuropathy who were unresponsive or intolerant to conventional therapy. Capsaicin is an alkaloid found in capsicum peppers and produces desensitization to noxious thermal, chemical, and mechanical stimuli when applied topically.
In 22 randomly assigned subjects, either capsaicin or vehicle cream was applied to painful areas 4 times/day. Pain measurements were recorded at baseline and at 2-wk intervals for 8 wk.
Capsaicin treatment was more beneficial than vehicle treatment in the overall clinical improvement of pain status, as measured by physician's global evaluation (P = 0.038) and by a categorical pain severity scale (P = 0.057). Decrease in mean pain intensity by a visual analogue scale was 16% in capsaicin-treated and 4.1% in vehicle-treated subjects. Mean pain relief on visual analogue scale was 44.6 and 23.2%, respectively. In a follow-up open-label study, approximately 50% of subjects reported improved pain control or were cured, and 25% each were unchanged or worse. A burning sensation at the application site was noted by some subjects but both its magnitude and duration decreased with time.
Results from this preliminary study suggest that topical 0.075% capsaicin may be of value in subjects with diabetic neuropathy and intractable pain.
We examined the immunohistochemical distribution of the arachidonate 12- and 15-lipoxygenases in animal and human lung tissue using a polyclonal anti-12/15-lipoxygenase antibody. Immunoblotting of whole cell extracts from bovine and human tracheal epithelial cells or from bovine leukocytes with the antibody (raised originally against purified porcine leukocyte 12-lipoxygenase) showed immunoperoxidase staining of a single protein band (Mr = 72,000), which comigrated with purified bovine 12-lipoxygenase. The antibody also immunoprecipitated both 12- and 15-lipoxygenase activities from cytosolic fractions of bovine and human tracheal epithelial cells. Immunohistochemistry of formaldehyde-fixed and paraffin-embedded bovine (and ovine and canine) trachea using the same polyclonal antibody and an indirect biotin-avidin-peroxidase detection system demonstrated specific staining of tracheal epithelium, polymorphonuclear and mononuclear leukocytes, and perineural cells. Less intense staining of submucosal glands and blood vessels was also observed. Lung sections demonstrated that the level of lipoxygenase antigen decreased markedly by the level of the bronchi and was absent in more distal airways. A similar pattern of immunostaining was found in human lung, except that airway smooth muscle was also weakly reactive, and polymorphonuclear (neutrophilic) leukocytes were unstained (in accordance with the low 12/15-lipoxygenase activity in this cell type). We conclude that animal and human epithelial 12/15-lipoxygenases share enzymatic, antigenic, and regional distribution characteristics and may therefore possess a common function in the pulmonary airway.
