Capsaicin activity

Matinelli S, Vaughan CW, Christie MJ, Connor M (2002) Capsaicin activation of glutamatergic synaptic transmission in the rat locus coeruleus in vitro. J Physiol 543 531-540 Martin BR, Mechoulam R, Razdan RK (1999) Discovery and characterization of endogenous cannabinoids. life Sd 65 573-595... 

Capsaicin activates receptors in trigeminal (cranial nerve V) and intestinal neurons. These include pain receptors located in the mouth, nose, stomach, and mucous membranes. Trigeminal neurons utihze substance P as their primary pain neurotransmitter. Capsaicin first induces the release of substance P from the neuron and then blocks the synthesis and transport of substance P to the effector side (Bernstein et al, 1981 Tominack and Spyker, 1987). Substance P depolarizes nemons to produce dilation of blood vessels, stimulation of smooth muscle, and activation of sensory nerve endings (Hehne et al, 1987 Tominack and... 

Capsaicin activates a nonselective cation channel in cultured neonatal rat dorsal root ganglion neurons, J. Neurosci. 1996, 16, 1659-1667. 

In some respects this stimulatory action was found to be tissue specific. In the monkey, capsaicin activated adenylate cyclase in membranes of anterior limbic cortex but not of frontal cortex (Ahn and Makman,... 

Horvath, K., Jancs6, G., and Wollemann, M., 1979, The effect of calcium on the capsaicin activation of adenylate cyclase in rat brain, Brain Res. 179 401-403. 

C. Capsaicin activates an ion-channel protein that modulates the transport of cations across cell membranes... 

Capsaicin is used topically for symptomatic relief of pain. Unlike other pain medications that decrease inflammation (NSAIDs) or prevent transmission (local anesthetics) and perception of pain (narcotics), capsaicin works on a special type of nociceptors at the origin of the pain signal. Capsaicin activates the capsaicin or vaniloid 1 receptor, which is a special type of temperature-sensitive transient receptor potential (TRP) non-selective ion channel (TTRPl). Capsaicin also induces release of substance P, which is responsible for runny nose, watery eyes, sweating, and gastric juice production. Capsaicin also releases endorphins however, it appears that this does not play a major role in pain relief by capsaicin. 

While a single dose of capsaicin activates pain, inflammation and hypersensitivity, repeated... 

Like all other RCAs, aerosol-dispersed OC causes erythema burning of the eyes, nose, and throat sneezing coughing and blepharospasm. Acute exposure to inhaled OCs results in pulmonary edema, bron-chospasm, respiratory arrest, hypertensive crises, and hyperthermia. OC causes excitement, convulsions, dyspnea, and death due to respiratory failure. While pepper spray is considered relatively safe, fatalities have been reported due to airway obstruction (Synman et al., 2001). Inhalation of capsaicin activates the Kratschmer reflex, as mentioned earlier, accompanied by bradycardia, apnea, and a biphasic rise and fall of aortic blood pressure. The pulmonary effects of capsaicin may be species-related. In guinea pigs exposed to capsaicin via aerosol, bronchoconstriction occurred, suggesting both a... 

Mediator-induced inflammatory processes can lead to increased vascular permeability, neurogenic inflammation of airways and blood vessels, chemotaxis, and bronchospasm (Smith and Topford, 1999). Furthermore, capsaicin activates the vanilloid receptor family TRPVl (transient receptor potential cation channel subfamily V) within sensory neurons. Activation of these receptors leads to prolonged refractory periods and to a nonconducting desensitization. One study suggests that TRPV pathways may not be enhrely responsible for all of the adverse reactions caused by capsaicin (Holzer, 1991). 

Eljamal M, Wong LB, Yeates DB. Capsaicin-activated bronchial- and alveolar-initiated pathways regulating tracheal eiliary beat frequeney. J Appl Physiol 1994 77 1239-1245. 

Capsaicin, an active ingredient in red pepper, is well known for its ability to release and deplete substance P in sensory C fibers. However, this action is not specific for substance P, as neurokinin A, calcitonin gene-related peptide (CGRP), and somatostatin also are released. 

Resiniferatoxin (RTX) is the toxin isolated from the spurge Euphorbia resinifera which is responsible for the powerful burning sensation and skin irritation induced by the milky sap of these plants. Like capsaicin, resiniferatoxin activates TRPV1 currents, but not the currents through other members ofthe TRPV subfamily. 

Members of the TRPV subfamily are activated by a broad range of stimuli including heat (TRPV1, TRPV2, TRPV3 and TRPV4), ligands such as capsaicin... 

TRPVl, also known as the capsaicin- or vanilloid-receptor, is a nonselective cation channel expressed e.g., in neurons of the dorsal root and trigeminal ganglions, which integrates multiple pain-producing stimuli including heat, protons, capsaicin, and resiniferatoxin. In addition, TRPVl currents can be activated by ananda-mide, protein kinase C (PKC), and by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2). 

TRPVl also plays a central role in intercellular pro-inflammatory feedback loops. An important example is mast cells and sensory nerves. Mast cells release tryptase that, in turn, activates the protease-activated receptor PAR-2 activation of PAR-2 then opens TRPVl via PKC [50]. In keeping with this, PAR-2 agonists reduce the heat activation threshold of TRPVl from 42 °C to below body temperature [51]. Excited nerve endings release SP that, as a positive feedback, binds to neurokinin NKl receptors on mast cells. Mast cells also express TRPVl [52]. Consequently, endovanilloids can act in concert to stimulate mast cells and activate capsaicin-sensitive nerve endings. Of relevance is the finding that PAR-2 is up-regulated in the bladder during experimental cystitis [53]. 

Nevertheless, RR is clearly a non-competitive antagonist that blocks the channel pore [2] with no effect on [ H]RTX binding [4]. RR was useful in dissecting responses mediated by capsaicin-sensitive nerves in vitro, but its use in animals was severely restricted by the toxicity (e.g. convulsive activity) that it caused [1]. 

The hit, SB-452533, (23a) was discovered by HTS of an in-house library at GSK [86]. Compound (23a) could potently and reversibly inhibit activation of TRPVl by capsaicin, low pH and heat. Quaternization of (23a) by N-methylation afforded (24), unlikely to cross the cell membranes, but that eould nevertheless retain a certain degree of inhibitory activity on TRPVl activation. When (24) was applied intracellularly, no activity could be detected. The binding of eaps-aicin to TRPVl has traditionally been considered intracellular, but this and other observations actually suggest a more complex situation. 

Another intriguing observation is that the female sex-hormone 17/i-estradiol (28) could dramatically potentiate capsaicin responses, whereas the male hormone testosterone had marginal inhibitory activity. Sex differences in pain responses have long been known, with women being more sensitive to capsaicin-induced pain than men [94]. The differential modulation of capsaicin responses by female and male hormones might provide a rationale to explain this observation. 

Functional TRPVl is expressed in keratinocytes, hair follicles, sebocytes and sweat gland cells [151, 152]. In organ cultures, activation by capsaicin of... 

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