μ-Opioid Receptor Activation Modulates Transient Receptor Potential Vanilloid 1 (TRPV1) Currents in Sensory Neurons in A Model of Inflammatory Pain

Abstract

Current therapy for inflammatory pain includes the peripheral application of opioid receptor agonists. Activation of opioid receptors modulates voltage-gated ion channels, but it is unclear whether opioids can also influence ligand-gated ion channels [e.g., the transient receptor potential vanilloid type 1 (TRPV1)]. TRPV1 channels are involved in the development of thermal hypersensitivity associated with tissue inflammation. In this study, we investigated -opioid receptor and TRPV1 expression in primary afferent neurons in the dorsal root ganglion (DRG) in complete Freund's adjuvant (CFA)-induced paw inflammation. In addition, the present study examined whether the activity of TRPV1 in DRG neurons can be inhibited by -opioid receptor (-receptor) ligands and whether this inhibition is increased after CFA inflammation. Immunohistochemistry demonstrated colocalization of TRPV1 and -receptors in DRG neurons. CFA-induced inflammation increased significantly the number of TRPV1-and -receptor-positive DRG neurons, as well as TRPV1 binding sites. In whole-cell patch clamp studies, opioids significantly decreased capsaicin-induced TRPV1 currents in a naloxone-and pertussis toxinsensitive manner. The inhibitory effect of morphine on TRPV1 was abolished by forskolin and 8-bromo-cAMP. During inflammation, an increase in TRPV1 is apparently rivaled by an increase of -receptors. However, in single dissociated DRG neurons, the inhibitory effects of morphine are not different between animals with and without CFA inflammation. In in vivo experiments, we found that locally applied morphine reduced capsaicin-induced thermal allodynia. In summary, our results indicate that -receptor activation can inhibit the activity of TRPV1 via G i/o proteins and the cAMP pathway. These observations demonstrate an important new mechanism underlying the analgesic efficacy of peripherally acting -receptor ligands in inflammatory pain.

Morphine peripheral analgesia depends on activation of the PI3Kγ/AKT/nNOS/NO/K ATP signaling pathway

“…Taken together, these results show that PI3Kγ is constitutively expressed in a significant proportion of primary nociceptive neurons, giving support to its participation in morphine peripheral analgesia. In functional terms, the expression of PI3Kγ in TRPV1 corroborates the idea that capsaicin-sensitive neurons mediate increased morphine antinociception during rat-paw inflammation and also that activation of opioid receptors inhibits TRPV1-mediated total whole-cell currents in a high number of primary nociceptive neurons (6,19).…”

“…Subsequent in vitro studies, which confirmed the ability of opioids to inhibit adenylyl-cyclase activity in dorsal root ganglion (DRG) neurons, reinforced the assumption that the peripheral action of morphine was caused by inhibition of adenylyl-cyclase activity (5,6). Nevertheless, it was striking that morphine still displayed peripheral activity in rats when given 2 hours after intraplantar injection of PGE 2 , a time when hypernociception was significant but adenylyl-cyclase activity seemed to be irrelevant for the maintenance of the process ( Fig.…”

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

“…Interactions between different opioid receptor types, possibly via heterodimerization, can facilitate coupling to Ca 2ϩ channels (Walwyn et al, 2005(Walwyn et al, , 2009). Activation of peripheral opioid receptors also suppresses tetrodotoxin-resistant Na ϩ channels (Gold and Levine, 1996), nonselective cation currents (Ingram and Williams, 1994), purinergic 2X receptor-mediated currents (Chizhmakov et al, 2005), as well as TRPV1 currents via G i/o and the cAMP/protein kinase A pathway (Chizhmakov et al, 2005;Endres-Becker et al, 2007). Colocalization of GIRK channels and -opioid receptors was shown on sensory nerve endings in the epidermis (Khodorova et al, 2003), but no direct evidence of functional coupling or modulation of GIRK channels in DRG neurons has been provided so far.…”

TRPV1 dans les neuropathies douloureuses

“…L'activation du récepteur SSTR4 (somatostatin receptor 4) induit un effet analgésique par une régulation négative de TRPV1 [9]. Lors d'une inflammation, l'activation des récepteurs opioïdes μ inhibe les courants induits par TRPV1 via des voies de transduction impliquant des protéines G i/o et l'AMPc [10]. Régulation du canal TRPV1.…”