TRPV1 Antagonists and Chronic Pain: Beyond Thermal Perception

Abstract

Abstract:In the last decade, considerable evidence as accumulated to support the development of Transient Receptor Potential Vanilloid 1 (TRPV1) antagonists for the treatment of various chronic pain conditions. Whereas there is a widely accepted rationale for the development of TRPV1 antagonists for the treatment of various inflammatory pain conditions, their development for indications of chronic pain, where conditions of tactical, mechanical and spontaneous pain predominate, is less clear. Preclinical localization and expression studies provide a firm foundation for the use of molecules targeting TRPV1 for conditions of bone pain, osteoarthritis and neuropathic pain. Selective TRPV1 antagonists weakly attenuate tactile and mechanical hypersensivity and are partially effective for behavioral and electrophysiological endpoints that incorporate aspects of spontaneous pain. While initial studies with TRPV1 antagonist in normal human subjects indicate a loss of warm thermal perception, clinical studies assessing allelic variants suggests that TRPV1 may mediate other sensory modalities under certain conditions. The focus of this review is to summarize the current perspectives of TRPV1 for the treatment of conditions beyond those with a primary thermal sensitivity. OPEN ACCESSPharmaceuticals 2012, 5 115

Analgesic transient receptor potential vanilloid‐1‐active compounds inhibit native and recombinant T‐type calcium channels

“…Our results demonstrate that capsaicin, capsazepine, BCTC, and A-889425 are effective Ca v 3 channel inhibitors at concentrations well below those used clinically to produce analgesia (Brandt, Beyer, & Stahl, 2012). Interestingly, Palvanil, AMG9810, and resiniferatoxin did not modulate Ca v 3 channels despite being structurally and chemically related to the other TRPV1-active compounds tested (Figure 2a).…”

Acute inflammation sensitizes knee-innervating sensory neurons and decreases mouse digging behavior in a TRPV1-dependent manner

“…Indeed, it has recently been shown that intra-articular administration 632 of a TRPV1 antagonist attenuated early osteoarthritic pain in a mono-sodium iodoacetate model 633 of osteoarthritis(Haywood et al, 2018). Historically in pre-clinical models, TRPV1 antagonists 634 attenuated thermal hyperalgesia, but their efficacy in mechanical hyperalgesia and ongoing pain is 635 unclear(Brandt et al, 2012). The peripherally restricted TRPV1 antagonist, A-425619, has been 636 previously shown to reverse thermal and mechanical hypersensitivity in rat CFA models and also 637 restore weight bearing ability in rat osteoarthritis models(Honore et al, 2005).…”

Pain sensitization by parathyroid hormone-related peptide via convergent phosphoregulation of TRPV1

“…The role of TRPV1 in inflammatory pain has been the thoroughly studied. Many different inflammatory mediators, including BK, PGE 2 and NGF have been shown to cause phosphorylation of TRPV1 and increase channel activity [81,[99][100][101].…”

“…Additionally, mildly acidic inflammatory conditions can decrease the activation thresholds of TRPV1 [102,103]. Furthermore, inhibition of TRPV1 can lead to decreases in thermal and mechanical hypersensitivity in animal models of inflammatory pain [99]. Early clinical trials with TRPV1 antagonists show that inhibiting TRPV1 results in decreased thermal pain perception [104].…”

“…More recent clinical studies have shown that high doses of capsaicin cream can be effective at reducing neuropathic pain [105]. Additionally, there are preclinical studies showing that both genetic ablation and pharmacological inhibition of TRPV1 can attenuate thermal hypersensitivity, as well as changes in TRPV1 expression in animal models of neuropathic pain [99].…”