TY - JOUR
T1 - Rapid modulation of μ-opioid receptor signaling in primary sensory neurons
AU - Berg, Kelly A.
AU - Patwardhan, Amol M.
AU - Sanchez, Teresa A.
AU - Silva, Yamille M.
AU - Hargreaves, Kenneth M.
AU - Clarke, William P.
PY - 2007/6
Y1 - 2007/6
N2 - 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.
AB - 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.
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U2 - 10.1124/jpet.106.116681
DO - 10.1124/jpet.106.116681
M3 - Article
C2 - 17347322
AN - SCOPUS:34248525078
SN - 0022-3565
VL - 321
SP - 839
EP - 847
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -