TRPV1 promotes opioid analgesia during inflammation

Abstract

Pain and inflammation are inherently linked responses to injury, infection, or chronic diseases. Given that acute inflammation in humans or mice enhances the analgesic properties of opioids, there is much interest in determining the inflammatory transducers that prime opioid receptor signaling in primary afferent nociceptors. Here, we found that activation of the transient receptor potential vanilloid type 1 (TRPV1) channel stimulated a mitogen-activated protein kinase (MAPK) signaling pathway that was accompanied by the shuttling of the scaffold protein β-arrestin2 to the nucleus. The nuclear translocation of β-arrestin2 in turn prevented its recruitment to the μ-opioid receptor (MOR), the subsequent internalization of agonist-bound MOR, and the suppression of MOR activity that occurs upon receptor desensitization. Using the complete Freund’s adjuvant (CFA) inflammatory pain model to examine the role of TRPV1 in regulating endogenous opioid analgesia in mice, we found that naloxone methiodide (Nal-M), a peripherally restricted, nonselective, and competitive opioid receptor antagonist, slowed the recovery from CFA-induced hypersensitivity in wild-type, but not TRPV1-deficient, mice. Furthermore, we showed that inflammation prolonged morphine-induced antinociception in a mouse model of opioid receptor desensitization, a process that depended on TRPV1. Together, our data reveal a TRPV1-mediated signaling pathway that serves as an endogenous pain-resolution mechanism by promoting the nuclear translocation of β-arrestin2 to minimize MOR desensitization. This previously uncharacterized mechanism may underlie the peripheral opioid control of inflammatory pain. Dysregulation of the TRPV1–β-arrestin2 axis may thus contribute to the transition from acute to chronic pain.

Myrcene and terpene regulation of TRPV1

“…There is a connection between adrenoreceptors and TRPV1, where the adrenoreceptor activation inhibits TRPV1, possibly via activation of a TRPV1-inhibiting PKA-mediated phosphorylation pathway [80]. Further complexity arises when we consider that naloxone inhibition may also indicate opioid receptor involvement, and functional interactions between opioid and TRPV1 receptors have been shown in nociceptive and neuroprotective pathways [58,[81][82][83]. One key aspect for further study is the dose-response relationship for myrcene (and other Cannabis components), and TRPV1.…”

Peripheral neurons: Master regulators of skin and mucosal immune response

“…In these particular conditions, the release of opioid peptide by innate immune cells was not spontaneous and required exogenous stimulation. Conversely, it was further reported that the spontaneous relief from inflammatory pain observed in the late phase of some inflammatory models, such as intra‐plantar injection of complete Freund's adjuvant (CFA) , collagen induced arthritis and DSS‐induced colitis was mainly dependent on the expression of Met‐enkephalin by effector CD4 + T cells . Proenkephalin mRNA were detected in antigen‐specific CD4 + T cells upon their activation by APCs within the draining lymph nodes.…”

Two Vanilloid Ligand Bindings Per Channel Are Required to Transduce Capsaicin-Activating Stimuli

“…Capsaicin is a lipophilic molecule that binds to the transmembrane domain of TRPV1, presumably aided by local lipid interactions provided by the membrane environment (Cao et al, 2013a,b;Hanson et al, 2015). The capsaicin receptor TRPV1 serves as a critical node in nociception, representing an attractive target for modifying pain sensations (Basso et al, 2019;Lee et al, 2019). Thus, further research into the TRPV1 channel would enhance our understanding of the thresholds or dynamic range of pain sensation and perhaps reveal potential therapeutic applications.…”