Activation of the transient receptor potential vanilloid‐1 (TRPV1) channel opens the gate for pain relief

Abstract

Pharmacological modulation of the transient receptor potential vanilloid-1 (TRPV1) receptor function offers a promising means of producing pain relief at the level of the primary sensory neuron. In this issue of the BJP, the pharmacological approaches and the available experimental data that focus on the TRPV1 receptor to achieve therapeutically useful alleviation of pain and inflammation are reviewed. The potentials to inactivate TRPV1 receptor function by site-and modality-specific TRPV1 antagonists, uncompetitive TRPV1 blockers and drugs interfering with TRPV1 sensitization, are evaluated. A crucial issue of producing pain relief at the level of the nocisensor remains whether it can be achieved solely through inactivation of the TRPV1 receptor or TRPV1 agonist-induced defunctionalization of the whole primary afferent neuron is required. The accumulated evidence indicates that both pharmacological modulation of the intracellular trafficking of the TRPV1 receptor and defunctionalization of the nocisensors by TRPV1 agonists are promising novel approaches to tame the TRPV1 receptor.

Roles of Glia, Immune Cells and the Thermo-TRP Channels, TRPV1, TRPA1 and TRPM8, in Pathological Pain

“…Quite recently, different clinical applications of vanilloid agonists for anti-nociceptive, antiinflammatory and anti-hyperalgesic effects via TRPV1 channels have been reported [94,95].…”

Competitive inhibition of TRPV1–calmodulin interaction by vanilloids

“…The affinity of TRPV1 for capsaicin has been shown to be dependent on the ability of the channel to bind CaM [20]. There are mechanisms for the vanilloid-induced neuronal dysfunction that are independent of direct channel regulation: disrupted axonal transport [21] and downregulated TRPV1 expression [22], where Ca 2+ homeostasis and regulation also appear pivotal [23]. The above literature findings led us to test the direct vanilloid-CaM interactions at the molecular level, which could interfere with Ca 2+ regulation, and hence with the TRPV1-mediated function of the sensory neurons.…”

Capsaicin-induced activation and chemical injury of nociceptive primary sensory neurons

“…Indeed, quantitative analysis of CTB-binding in cultured DRG neurons revealed a marked and significant, dose-dependent decrease in membrane GM1 level after D-PDMP treatment which may affect the membrane localization of and signaling through the TRPV1 receptor (Holzer, 1991;Jancsó et al, 2008). Similar studies focusing on the depletion of membrane cholesterol and sphingomyelin, other important components of lipid microdomains, have also been shown to reduce the sensitivity of cultured DRG neurons to capsaicin (Liu et al, 2006;Szoke et al, 2010).…”

“…Several molecular pathways have revealed which regulate the sensitivity of the TRPV1 receptor to capsaicin and other modulators (Bonnington and McNaughton, 2003;Chuang et al, 2001;Julius and Basbaum, 2001;Nagy et al, 2004;Tominaga et al, 1998) but the possible role of gangliosides in the regulation of capsaicin sensitivity has not been considered, yet. The morphological and neurochemical changes occurring in primary afferent neurons after peripheral nerve injuries led us to suggest that changes in the ganglioside metabolism of these neurons may modulate their nociceptive function (Jancsó et al, 2008;Jancsó et al, 2002;Sántha and Jancsó, 2003).…”