Results: 4

1.
Figure 1

Figure 1. From: TRP Channels in Pain and Inflammation: Therapeutic Opportunities.

Chemical structure of capsaicin (top) and resiniferatoxin (RTX) (bottom) illustrating common active moieties including –methoxy and hydroxyl groups (circled). Although both function as agonists at the TRPV1 receptor, RTX has higher potency and a characteristically slow but persistent activation.

Mark A. Schumacher. Pain Pract. ;10(3):185-200.
2.
Figure 2

Figure 2. TRPV1 protein topology. From: TRP Channels in Pain and Inflammation: Therapeutic Opportunities.

TRPV1 is distinguished by six transmembrane spanning regions flanked by two intracellular domains (N) amino-terminal and (C) carboxyl-terminal. The N-terminal domain includes three ankyrin (A) repeat domains that may function in receptor modulation. A pore loop domain is predicted between the fifth and sixth transmembrane spanning region. It is proposed that at least four such subunits assemble to form a functional channel complex. Formation of hetermomeric channel complexes incorporating TRPV1 plus other TRPV1 splice variant and/or TRP – channel subunits have been proposed.

Mark A. Schumacher. Pain Pract. ;10(3):185-200.
3.
Figure 3

Figure 3. Mechanisms of TRPV1 mediated inflammatory hyperalgesia and pain transduction (top). From: TRP Channels in Pain and Inflammation: Therapeutic Opportunities.

Following tissue injury, local tissue responds with increased production and accumulation of inflammatory compounds that activate/sensitize TRPV1. Nociceptive terminals derived from C- and A-delta fibers are interposed with skin fibroblasts, mast cells and the microvasculature. Following injury or inflammation terminals depolarize releasing neuropeptides substance-P (SP) and calcitonin gene related peptide (CGRP) which produces vascular leak and edema. Bradykinin (BK) cleaved from circulating kallikreins and nerve growth factor (NGF) produced by fibroblasts an infiltrating PBMs both activate and sensitize nociceptor terminals. NGF produces additional sensitization through the degranulation of mast cells containing serotonin (5-HT) and histamine. NGF and cytokines are associated with the accumulation of neutrophils and lymphocytes that participate in the maintenance of sensitization -hyperalgesia. (Bottom) Hypothetical nociceptor terminal expressing TRPV1 activated by capsaicin (peppers), noxious heat (fire) and extracellular protons (H+). The resulting inward calcium current depolarizes terminal initiating action potentials that signal higher centers (not shown). Inflammatory mediators such as bradykinin (BK), ATP, trypsins, and NGF act through various secondary messenger systems to activate or sensitize TRPV1, resulting in pain and hyperalgesia.

Mark A. Schumacher. Pain Pract. ;10(3):185-200.
4.
Figure 4

Figure 4. Mechanisms of topical capsaicin-mediated analgesia. From: TRP Channels in Pain and Inflammation: Therapeutic Opportunities.

Repeat application of capsaicin or other vanilloid – like compounds can produce a number of local effects on TRPV1 – expressing nociceptor terminals: (A) Desensitization is a calcium-dependent phenomenon where application of capsaicin leads to a decrease in inward current response during continued capsaicin application. When capsaicin is applied at repeated intervals, each subsequent response becomes smaller and is often referred to as tachyphylaxis. It is proposed that under these conditions, TRPV1 may also be refractory to the effect of inflammatory mediators and intracellular secondary messengers. (B) Repeated or prolonged application of capsaicin can produce nociceptor dysfunction. Under this condition, which may be secondary to an influx and/or excess of store-released calcium, other pain transducing receptor – channels may be inactivated. This could explain analgesic effects that are beyond the scope of TRPV1 function. (C) Depletion of neuropeptides (Substance –P, CGRP) from nociceptive terminal is evoked by capsaicin and high dose or repeat applications have been shown to deplete both central and peripheral terminals. Although the activity of Substance –P has been show to play a key role in facilitating nociceptive neurotransmission in the dorsal horn of the spinal cord, blockade of the Substance –P receptor (NK1R) has failed to show analgesia in humans. (D) Destruction of TRPV1-expressing nociceptive terminals has been the most reliable marker correlating the application of vanilloid –like compounds and analgesia. Although a number of mechanisms have been proposed, vanilloid – induced apoptosis appears to be the likely mechanism.

Mark A. Schumacher. Pain Pract. ;10(3):185-200.

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