Stimulation of peripheral nociceptor endings by low dose morphine and its signaling mechanism

Takeshi Ono, Makoto Inoue, M. Harunor Rashid, Koji Sumikawa, Hiroshi Ueda

Research output: Contribution to journalArticlepeer-review


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 ( application of morphine produced flexor response in a dose-dependent manner from 0.1 to 1000amol. The μ-opioid receptor (MOP-R) agonist [D-Ala2,N-Me-Phe4,Gly5-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 Gαi/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(β-aminoethyl ether) N,N,N′,N′-tetraacetic acid (EGTA), a Ca2+ chelating agent; xestospongin C, a membrane-permeable inositol trisphosphate (InsP3) receptor antagonist inhibited the morphine-flexor responses. However, thapsigargin, a depletor of intracellular Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)399-407
Number of pages9
JournalNeurochemistry International
Issue number6
StatePublished - Dec 2002
Externally publishedYes


  • Morphine
  • Nociception
  • Substance P
  • μ-Opioid receptor (MOP-R)

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology


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