title: Stimulation of peripheral nociceptor endings by low dose morphine and its signaling mechanism.
abstract: In this report, we demonstrated that peripheral application of very low dose (amol ranges) of morphine induced flexor response through a substance P (SP) release at the nociceptor endings in mice. The intraplantar (i.pl.) application of morphine produced flexor response in a dose-dependent manner from 0.1 to 1000amol. The mu-opioid receptor (MOP-R) agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) also produced dose-dependent flexor response in same dose ranges. Morphine-induced flexor responses were markedly inhibited by naloxone and D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP) both MOP-R antagonists and by intrathecal injection of antisense oligodeoxynucleotide (AS-ODN) for MOP-R which is expected to reduce the receptor expression in sensory nerve endings. Prior incubation with capsaicin, a depletor of SP from polymodal C fibers and [(+)-(2S,3S)-(2-methoxybenzylamino)-2-phenylpiperidine] (CP-99994), a tachykinin 1 receptor antagonist, also blocked the morphine-induced flexor responses. Moreover, pertussis toxin (PTX) which inactivates G(alpha)(i/o); [(1-[6-([(17b)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino)hexyl]-1H-pyrrole-2,5-dione)] (U-73122), an inhibitor of phospholipase C (PLC); ethyleneglycol-bis(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA), a Ca(2+) chelating agent; xestospongin C, a membrane-permeable inositol trisphosphate (InsP(3)) receptor antagonist inhibited the morphine-flexor responses. However, thapsigargin, a depletor of intracellular Ca(2+) concentration and diphenhydramine, a histamine (His) H1 receptor antagonist, were unable to block the morphine-induced flexor responses. These results suggest that extremely low doses of morphine can stimulate sensory nerve endings through activation of peripheral MOP-R and its downstream mechanisms include activation of PLC through a SP release from polymodal C fibers.
authors.affiliation: Department of Anesthesiology, Nagasaki University School of Medicine, Nagasaki, Japan
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ono
authors.forename: Makoto
authors.initials: M
authors.lastname: Inoue
authors.forename: M Harunor
authors.initials: MH
authors.lastname: Rashid
authors.forename: Koji
authors.initials: K
authors.lastname: Sumikawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ueda
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000502:physiology; D006614:Hindlimb; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage* / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects* / Q000502:physiology*; D037342:Pertussis Toxin / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013373:Substance P / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D013373:Substance P; D009020:Morphine; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D002118:Calcium