Transient receptor potential channels in pain and inflammation: therapeutic opportunities

Abstract

In ancient times, physicians had a limited number of therapies to provide pain relief. Not surprisingly, plant extracts applied topically often served as the primary analgesic plan. With the discovery of the capsaicin receptor (transient receptor potential cation channel, subfamily V, member 1 [TRPV1]), the search for "new" analgesics has returned to compounds used by physicians thousands of years ago. One such compound, capsaicin, couples the paradoxical action of nociceptor activation (burning pain) with subsequent analgesia following repeat or high-dose application. Investigating this "paradoxical" action of capsaicin has revealed several overlapping and complementary mechanisms to achieve analgesia including receptor desensitization, nociceptor dysfunction, neuropeptide depletion, and nerve terminal destruction. Moreover, the realization that TRPV1 is both sensitized and activated by endogenous products of inflammation, including bradykinin, H+, adenosine triphosphate, fatty acid derivatives, nerve growth factor, and trypsins, has renewed interest in TRPV1 as an important site of analgesia. Building on this foundation, a new series of preclinical and clinical studies targeting TRPV1 has been reported. These include trials using brief exposure to high-dose topical capsaicin in conjunction with prior application of a local anesthetic. Clinical use of resiniferatoxin, another ancient but potent TRPV1 agonist, is also being explored as a therapy for refractory pain. The development of orally administered high-affinity TRPV1 antagonists holds promise for pioneering a new generation of analgesics capable of blocking painful sensations at the site of inflammation and tissue injury. With the isolation of other members of the TRP channel family such as TRP cation channel, subfamily A, member 1, additional opportunities are emerging in the development of safe and effective analgesics.

Figure 1

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.

Figure 2. TRPV1 protein topology

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.

Figure 3. Mechanisms of TRPV1 mediated inflammatory hyperalgesia and pain transduction (top)

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.

Figure 4. Mechanisms of topical capsaicin-mediated analgesia

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.