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

Neurochem Int. 2002 Dec;41(6):399-407. doi: 10.1016/s0197-0186(02)00047-5.


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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / administration & dosage*
  • Analgesics, Opioid / pharmacology
  • Animals
  • Calcium / physiology
  • Dose-Response Relationship, Drug
  • GTP-Binding Proteins / physiology
  • Hindlimb
  • Male
  • Mice
  • Morphine / administration & dosage*
  • Morphine / pharmacology
  • Muscle Contraction / drug effects
  • Muscle Contraction / physiology
  • Nociceptors / drug effects*
  • Nociceptors / physiology*
  • Pertussis Toxin / pharmacology
  • Receptors, Opioid, mu / physiology
  • Signal Transduction / physiology*
  • Substance P / metabolism


  • Analgesics, Opioid
  • Receptors, Opioid, mu
  • Substance P
  • Morphine
  • Pertussis Toxin
  • GTP-Binding Proteins
  • Calcium