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CELLULAR AND MOLECULAR

Rapid Modulation of µ-Opioid Receptor Signaling in Primary Sensory Neurons

Departments of Pharmacology (K.A.B., T.A.S., Y.M.S., K.M.H., W.P.C.) and Endodontics (A.M.P., K.M.H.), University of Texas Health Science Center, San Antonio, Texas

Management of pain by opioid analgesics is confounded by central adverse effects that limit clinical dosages. Consequently, there is considerable interest to understand peripheral analgesic effects of opioids. The actions of opioids on peripheral sensory neurons have been difficult to study because of a general lack of effect of opioid agonists on nociceptor function in culture despite documented presence of opioid receptors. In this study, the µ-opioid receptor agonist, [D-Ala²,N-MePhe⁴,Gly-ol⁵]-enkephalin (DAMGO), did not alter guanosine 5'-O-(3-[³⁵S]thio)-triphosphate (GTP[³⁵S]) binding, adenylyl cyclase activity, or neuropeptide release in primary cultures of rat trigeminal ganglion (TG). However, after brief exposure to bradykinin (BK), DAMGO stimulated GTP[³⁵S] binding and inhibited both prostaglandin E₂ (PGE₂)-stimulated adenylyl cyclase activity and BK/PGE₂-stimulated neuropeptide release. The effect of BK was blocked by the B₂ antagonist HOE 140 [D-Arg[Hyp³,Thi⁵,D-Tic⁷,Oic⁸]-bradykinin], but not by the B₁ antagonist, Lys-[Leu8]des-Arg9-BK, and was mimicked by the protease-activated receptor-2 agonist, Ser-Leu-Ile-Gly-Arg-Leu-NH₂, and by activation of protein kinase C (PKC) or by administration of arachidonic acid (AA). The enhanced responsiveness of µ-opioid receptor signaling by BK priming was blocked by both cyclooxygenase and PKC inhibitors; however, the effect of AA was blocked only by a cyclooxygenase inhibitor. The results indicate that µ-opioid receptor signaling in primary sensory TG neurons is enhanced by activation of phospholipase C-coupled receptors via a cyclooxygenase-dependent AA metabolite that is downstream of PKC.

Address correspondence to: Dr. William P. Clarke, Department of Pharmacology, MS 7764, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900. E-mail: clarkew{at}uthscsa.edu