Modulation of TRPV1 by CB1 receptor activation

A number of studies in native tissues have addressed the question of CB1 receptor-mediated modulation of TRPV1 responses in nociceptive pathways. These studies have yielded evidence both supporting and negating CB1 receptor-mediated modulation of TRPV1 receptor responses. Certain studies provide functional data to suggest that CB1 receptors may not be located on small-diameter nociceptive primary afferent fibers the cannabinoid receptor agonist, CP55940 (100 nM), significantly inhibits...

Conclusion

Many regions and amino acids involved in TRPV1 function have been identified. Given that TRPV1 is a key molecule in peripheral nociception, these regions and amino acids could prove useful for the development of novel anti-nociceptive or anti-inflammatory agents. Crystallographic analysis promises to provide even more information about the structural determinants of TRPV1 functionality. I thank Dr M.J. Caterina (Johns Hopkins University School of Medicine) for his critical reading of the...

Functional desensitization of polymodal nociceptors

Functional desensitization is achieved when vanilloid agonists are applied at concentrations several-fold higher than that required for the threshold of stimulation. Capsaicin-sensitive polymodal nociceptors show decreased responses to various noxious stimuli detected by these neurons, like bradykinin, heat, and high-threshold mechanical stimuli 75-81 . Capsaicin-insensitive neurons reacting to cold and low-threshold mechanical stimuli are, however, not affected, indicating that the functional...

Secondary mechanical hyperalgesia

Different forms of secondary mechanical hyperalgesia have been characterized. The secondary hyperalgesia is predominantly a central phenomenon reflecting neuroplastic changes in spinal cord neurons. Secondary hyperalgesia can be separated into an area of brush-evoked hyperalgesia (dynamic hyperalgesia or allo-dynia) where on-going pain seems essential and a slightly larger area of punctuate hyperalgesia (static hyperalgesia) 33, 34 . Allodynia is normally assessed by stroking the skin with a...

Innervation of other organs

Capsaicin evokes vasodilatation in the dura mater of the rat 28 , presumably by stimulation of capsaicin-sensitive afferents and the resultant release of vasoactive neuropeptides. TRPV1, which can be stimulated by alcohol 29 , may be a major player in ethanol-evoked headaches and migraines these are strongly associated with dural vasodilatation which can be evoked by CGRP release from TRPV1- TRPV1 in the dura. (A-C) Whole mounts of rat dura stained with (A) mouse anti-fi-III tubulin to reveal...

Anandamide endocannabinoid and endovanilloid

The endocannabinoid system comprises two known receptors (CBj and CB2), a family of endogenous ligands, and specific molecular machinery for the synthesis, transport, and inactivation of cannabinoid ligands 1 . N-Arachidonoyl-ethanolamide (anandamide) (Fig. 1) is known as an endocannabinoid, as defined by its ability to be produced endogenously and to bind to and activate cannabinoid CB1 and CB2 receptors (see 1 ). Since its discovery, anandamide has been shown to have numerous physiological...

Electrophysiological methods to assess hyperalgesia

Microneurography is the direct stimulation of or recording from single nerve fibers and has been used to characterize relationships between neuronal firing and perception intensity and quality. This method may identify activation patterns of nociceptive AS- and C-fibers and of different classes of nociceptors, although the vast Repetitive punctuate stimulation with a von Frey hair within the area with hyperalgesia is illustrated. The device stimulates with a fixed time period in contact with...

ANKTM1 channel

It is known that the plant-derived cannabinoid, A9-tetrahydrocannabinol (THC), has analgesic and anti-inflammatory properties, which may be mediated by CB1 receptors present on primary afferent sensory neurons. However, THC appears to retain an analgesic effect in CBj - - mice. In addition, cannabidiol is anti-inflammatory and analgesic and does not share the ability of THC to bind to and activate CBj receptors. These data raise the possibility of a non-CB1 receptor-mediated action of...

References

1 Jancso N, Jancso A (1949) Desensitization of sensory nerve endings in Hungarian . Kiserletes Orvostudomany 2 (Suppl) 15 2 Buck SH, Burks TF (1986) The neuropharmacology of capsaicin a review of some recent observations. Pharmacol Rev 38 179-226 3 Holzer P (1991) Capsaicin cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol Rev 43 143-120 4 Szallasi A, Blumberg PM (1999) Vanilloid (capsaicin) receptors and mechanisms. Pharmacol Rev 51 159-212 5 Szallasi...

Capsaicin and the gut not just a matter of taste

Few would deny that seasoning heightens the joy of a meal, and history tells us that wars have been fought to ensure an unbroken supply of spices. One of the most unusual seasonings is the vanilloid derivative capsaicin, the pungent ingredient in a wide variety of red peppers of the genus Capsicum including chilli and jalape o, given that the sensory experience associated with its intake ranges from pleasant to painful. This is probably a reason why mankind is divided into people who love and...

Historical introduction

There are compounds that can selectively desensitize sensory nerve endings to noxious chemical stimuli without causing local anesthesia Capsaicin is the paradigm of such desensitizing agents. Capsaicin effects last for days and protect against various chemicals With these words, the late Nicholas (Miklos) Jancso opened a new chapter in sensory pharmacology in 1949 1 . It is a misfortune of the scientific world that Jancso chose to publish his seminal observation in his native Hungarian language...

Central nervous system distribution

Multiple lines of evidence point to TRPV1 expression in the brain. The direct action of capsaicin on the preoptic anterior hypothalamus (POAH) is responsible for the hypothermia evoked by systemic capsaicin. This functional effect is abolished in TRPV1-knockout animals, supporting a TRPV1-evoked mechanism 10 . Capsaicin causes ultrastructural damage to some hypothalamic neurons and 3H RTX-binding sites 42 , TRPV1 mRNA and TRPV1 immunoreactivity 43 have all been detected in the hypothalamus....

Vulvodynia and mucosal disorders

Vulvodynia is a pain syndrome characterized by painful burning sensations, allody-nia, hyperalgesia and itching, usually localized in the region of the vulvar vestibules 72 . Vulvar tissue arises from the same urogenital progenitors as bladder hence it might not be surprising to find parallels involving hyperproliferation of nociceptive fibers. In vulvodynia patients, the hypersensitivity of vulvar C-fibers is well documented 73, 74 , and immunohistological evaluation of small-diameter...

TRPV1 expression outside the nervous system

As well as being expressed on the sensory innervation of the airways, TRPV1 is also expressed on airways epithelial cells, and activation of TRPV1 by particulate matter induces apoptosis, which may be an important mechanism for particulate matter damage to the airways 47 . Air pollutants are thought to cause a reduced immune function and lowered resistance to infection as well as hypersensitivity to allergens and may exacerbate asthma and chronic obstructive pulmonary disease (COPD)....

Clinical experience with intravesical TRPV1 agonists in neurogenic forms of bladder overactivity

Spinal-cord injury patients presenting high urinary frequency, urgency and incontinence frequently require vigorous treatment to improve their social integration and quality of life. Anticholinergic or smooth muscle-relaxant drugs are among the firstline therapeutic options. However, as these compounds do not completely avoid frequent voidings or non-voluntary urine loss without giving rise to unacceptable side effects 9 , clinical trials with intravesical TRPV1 agonists were pushed forward in...

Rationale for intravesical application of TRPV1 agonists

Clinical interest on TRPV1 agonists for the treatment of bladder diseases started with the observation that reflex bladder contractions triggered by bladder filling in intact or spinally transected cats had distinct sensibilities to systemic capsaicin. In spinally transected cats, but not in intact cats, reflex bladder contractions were completely suppressed by the neurotoxin 1 . The identification of two neuronal pathways involved in micturition control offered a solid explanation to this...

Migraine and headache

Civamide is the generic name for cis-capsaicin (which is also known as zucapsaicin see Fig. 3). trans-Capsaicin is the naturally occurring form of capsaicin, whereas cis-capsaicin must be synthesized 85 . Following systemic administration, civamide has been reported to be active in rodent models of nociceptive and neuropathic pain 86 . Subsequently, civamide has been investigated clinically for a number of indications, including prophylaxis of migraine, episodic cluster headache and OA (see...

TRPV1 ligands and the airway inflammatory response

In addition to the stimulation of airway C-fibres, capsaicin has also been shown to have effects on the inflammatory response as assessed in human cell-based assay systems. Thus, capsaicin has been shown to interact with TRPV1 expressed by BEAS-2B and other airway epithelial cells to cause the calcium-dependent production of cytokines and, conversely, calcium-independent cell death. The mechanisms of these cellular responses to capsaicin appear to proceed via distinct cellular pathways, but...

NADA and TRVP1

NADA (Fig. 1) has been identified in nervous tissue 10 . This novel endovanilloid is produced in highest concentrations in the striatum, hippocampus, and cerebellum. In HEK-293 cells overexpressing TRPV1 receptors, NADA increases intracellular Ca2+ levels with an EC50 of approx. 50 nM that is comparable to that obtained with capsaicin. In cultured DRG neurons, NADA increases intracellular Ca2+ levels with an EC50 of approx. 800 nM, an effect that is inhibited by capsazepine and iodoR-TX. The...

Other possible applications of intravesical TRPV1 agonists

Trpv1 The Spinal Cord

Intravesical administration of capsaicin 6 or RTX 7 can prevent pain induced by acute bladder inflammation in the rat, as shown by the suppression of c-fos gene expression in the spinal cord. An eventual analgesic effect of intravesical vanilloids in pain generated by chronic inflammatory bladder conditions would, therefore, be extremely relevant in a clinical setting. Chronic inflammatory pain is frequently disproportional to the intensity of the stimulus and is more resistant to common...

Specific contributions of TRPV1 to GI function in health and disease

Primicias Biblicas

Capsaicin as a neuropharmacology tool demonstration that sensory neurons are important for gut function Red pepper has been used since ancient times as both a spice and a treatment for GI disease. However, the biological actions of its pungent ingredient were not understood before capsaicin was found to be a selective stimulant of primary afferent neurons. The immediate but transient excitation is followed by a long-lasting desensitization of sensory neurons to capsaicin and other stimuli 27,...

Nociceptor hyperactivity

Nociceptors Cell

Desensitization of nociceptive nerve fibers may constitute an important therapeutic intervention if they are hyperactive. Following acute injury, the basis for the hyper-activity and or hypersensitivity of nociceptive nerve endings in affected tissues is well established 3 , and the protective behaviors which result from nociceptor hyperactivity are considered fundamental to tissue repair and avoidance of additional damage. Still, TRPV1-agonist-based therapies are being developed for acute...

TRPV1 antagonists

It is becoming increasingly apparent that broad in vitro antagonist activity against multiple modes of TRPV1 activation (i.e. capsaicn-site agonists, low pH and heat) may be an important predictor of in vivo efficacy in animal models of pain (see below). While some of these molecules have been tested against these various mechanisms of TRPV1 activation, many still require further pharmacological characterization. A clear understanding at the molecular level, in conjunction with pharmacokinetic...

Species differences in selectivity of TRPV1 to ligands

The early analysis of capsaicin sensitivity revealed marked differences in sensitivity. Whereas capsaicin is pungent for people or rats, chickens and rabbits do not respond. In addition, human and rat TRPV1 show differences in ligand recognition. Several groups compared the homologs of TRPV1 from these various species, identified the specific differences in TRPV1 sequence between them, and used site-directed mutagenesis to evaluate the role of specific residues in TRPV1 on ligand responsiveness...

Diversity of structures active on TRPV1

Malen Nach Zahlen

A dominant theme emerging from the analysis of vanilloid action is that every aspect shows great complexity. An implication, of course, is that this diversity provides extraordinary opportunities for pharmacological exploitation. One aspect of this diversity is the great variation in structures that bind to TRPV1 through the capsaicin RTX-recognition site. The standard concept of the structural features involved in binding is that presented in an elegant series of papers by Walpole et al. 5-7 ....