Inhibition of neurokinin-1-substance P receptor and prostanoid activity prevents and reverses the development of morphine tolerance in vivo and the morphine-induced increase in CGRP expression in cultured dorsal root ganglion neurons

Eur J Neurosci. 2003 Sep;18(6):1572-83. doi: 10.1046/j.1460-9568.2003.02887.x.


Chronic treatment with opioid drugs such as morphine leads to the development of tolerance, which manifests as a loss of drug potency. The mechanisms underlying this phenomenon are poorly understood, but recent evidence suggests that increased activity of nociceptive sensory transmitters [calcitonin gene-related peptide (CGRP) and substance P] and other signalling messengers (prostaglandins) contribute to its development. Chronic intrathecal morphine administration to rats for 7 days produced analgesic tolerance. Co-administration of SR140333, a selective substance P receptor (neurokinin-1) antagonist, or nimesulide, a cyclooxygenase-2-selective inhibitor, augmented the acute effects of morphine, prevented morphine tolerance and reversed established tolerance. In cultured adult dorsal root ganglion neurons, exposure to morphine for 5 days increased the number of neurons expressing CGRP immunoreactivity. Co-exposure with the peptide CGRP receptor antagonist CGRP8-37, SR140333 or nimesulide prevented the morphine-induced increase in the expression of CGRP immunoreactivity. Additionally, BIBN4096BS, a nonpeptide CGRP receptor antagonist, stereoselectively produced similar effects. In summary, this investigation demonstrates that activity of CGRP and substance P contributes to both the induction and expression of opioid analgesic tolerance. Additionally, it highlights the involvement of prostaglandins generated by spinal cyclooxygenase-2 activity in the genesis of opioid tolerance. The neuropeptide and prostanoid activity contributing to tolerance is expressed at the level of the primary afferents terminating in the spinal cord. The combination of opioids with agents that block this activity may represent a useful strategy for the prevention as well as the reversal of clinical opioid tolerance.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal
  • Calcitonin Gene-Related Peptide / metabolism*
  • Calcitonin Gene-Related Peptide Receptor Antagonists
  • Cell Count
  • Cells, Cultured
  • Cyclooxygenase Inhibitors / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Interactions
  • Drug Tolerance / physiology
  • Ganglia, Spinal / cytology
  • Immunohistochemistry
  • Male
  • Morphine / adverse effects
  • Morphine / pharmacology*
  • Morphine Dependence
  • Neurokinin-1 Receptor Antagonists
  • Neurons / drug effects*
  • Neurons / metabolism
  • Pain Measurement / drug effects
  • Piperidines / pharmacology*
  • Prostaglandins / metabolism*
  • Quinuclidines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Calcitonin Gene-Related Peptide / agonists
  • Receptors, Neurokinin-1 / metabolism*
  • Spinal Cord / drug effects
  • Sulfonamides / pharmacology
  • Time Factors


  • Calcitonin Gene-Related Peptide Receptor Antagonists
  • Cyclooxygenase Inhibitors
  • Neurokinin-1 Receptor Antagonists
  • Piperidines
  • Prostaglandins
  • Quinuclidines
  • Receptors, Calcitonin Gene-Related Peptide
  • Receptors, Neurokinin-1
  • Sulfonamides
  • SR 140333
  • Morphine
  • Calcitonin Gene-Related Peptide
  • nimesulide