Rapid modulation of μ-opioid receptor signaling in primary sensory neurons

Kelly A. Berg, Amol M. Patwardhan, Teresa A. Sanchez, Yamille M. Silva, Kenneth M. Hargreaves, William P. Clarke

Research output: Contribution to journalArticlepeer-review

55 Scopus citations


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-ol 5]-enkephalin (DAMGO), did not alter guanosine 5′-O-(3-[ 35S]thio)-triphosphate (GTPγ[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 GTPγ[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,Thi 5,DTic7, 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.

Original languageEnglish (US)
Pages (from-to)839-847
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - Jun 2007

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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