Received for publication May 30, 2006.
Revised September 27, 2006.
Accepted for publication September 27, 2006.

µ receptor activation modulate 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. Here, we investigated µ-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 µ receptor ligands and whether this inhibition is increased after CFA inflammation. Immunohistochemistry demonstrated co-localization of TRPV1 and µ receptors in DRG neurons. CFA- induced inflammation increased significantly the number of TRPV1- and µ 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 toxin-sensitive 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 µ 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 µ 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 µ receptor ligands in inflammatory pain.

Key words: Opioid, Capsaicin/vanilloid, Gi family, Protein Kinase A, Immunocytochemistry, Receptor binding studies

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