Nociceptive TRP Channels: Sensory Detectors and Transducers in Multiple Pain Pathologies

Abstract

Specialized receptors belonging to the transient receptor potential (TRP) family of ligand-gated ion channels constitute the critical detectors and transducers of pain-causing stimuli. Nociceptive TRP channels are predominantly expressed by distinct subsets of sensory neurons of the peripheral nervous system. Several of these TRP channels are also expressed in neurons of the central nervous system, and in non-neuronal cells that communicate with sensory nerves. Nociceptive TRPs are activated by specific physico-chemical stimuli to provide the excitatory trigger in neurons. In addition, decades of research has identified a large number of immune and neuromodulators as mediators of nociceptive TRP channel activation during injury, inflammatory and other pathological conditions. These findings have led to aggressive targeting of TRP channels for the development of new-generation analgesics. This review summarizes the complex activation and/or modulation of nociceptive TRP channels under pathophysiological conditions, and how these changes underlie acute and chronic pain conditions. Furthermore, development of small-molecule antagonists for several TRP channels as analgesics, and the positive and negative outcomes of these drugs in clinical trials are discussed. Understanding the diverse functional and modulatory properties of nociceptive TRP channels is critical to function-based drug targeting for the development of evidence-based and efficacious new generation analgesics.

Macrophage angiotensin II type 2 receptor triggers neuropathic pain

“…Similar to MΦ infiltration in nerve injury/ neuropathy, MΦs and other immune cell infiltration has been well characterized in the CFA-induced model of inflammation (24). Furthermore, accumulation of a wide variety of inflammatory mediators that sensitize multiple pain-transducing receptors/ channels, such as TRPs and Na v , are considered to constitute inflammatory thermal and mechanical pain mechanisms (32,47). This, in combination with our observation that Ang II levels are unchanged in CFA versus saline-injected hindpaws, suggests a lack of AT2R activation at the site of CFA-induced inflammation, which would preclude the effectiveness of AT2R antagonism for inflammatory pain.…”

“…We next investigated the involvement of sensory transient receptor potential (TRP) channels in nerve injury-induced mechanical and cold hypersensitivity. Both TRPV1 and TRPA1 have been implicated in mechanical hypersensitivity (32,33), and in addition, TRPA1 is involved in cold hypersensitivity in experimental nerve injury/neuropathic pain states in mice (32,34,35). Systemic administration of a TRPA1 antagonist (A967079), but not TRPV1 antagonist (AMG9810), attenuated SNI-induced hindpaw mechanical hypersensitivity ( Fig.…”

Neuropathic Pain: Central vs. Peripheral Mechanisms

“…Both nerve damage/injury and the increased inflammatory microenvironment have been shown to upregulate the expression of these predominant sensory TRP channels, which in addition to functional changes lead to increases in the magnitude and duration of hyperexcitability of nerve fibers [reviewed in [38]. A large number of studies utilizing genetically modified mice lacking specific functional TRP channels and with the use pharmacological blockers of individual TRP channels have shown their critical involvement in peripheral nerve fiber excitation and neuropathic pain-related behaviors in rodent models (reviewed in [38,40]). …”

Diverse TRPV1 responses to cannabinoids

“…Channels of the Transient Receptor Superfamily (TRP), such as TRPV1, TRPM8, and TRPA1, are non-selective cation channels that conduct calcium and sodium into a range of cell types in mammals. They are present on sensory neurons, and were initially identified as having a role in nocioception because of their responsiveness at the molecular level to plant secondary metabolites that are nocimimetic (e.g., Capsaicin) and to compounds that are otherwise pungent and mimic burning or cooling sensations (e.g., allicin, cinnamaldehyde, menthol) [31][32][33][34][35][36]. Several of these channels are targets for cannabinoids including THC, CBD and CBN and some minor Cannabis compounds [37][38][39][40][41][42][43][44].…”