Role of opioid receptors in neurogenic dural vasodilation and sensitization of trigeminal neurones in anaesthetized rats

Br J Pharmacol. 2001 Jul;133(6):807-14. doi: 10.1038/sj.bjp.0704136.


Migraine headache is thought to be caused by a distension of meningeal blood vessels, the activation of trigeminal sensory neurones and the the development of a central sensitization within the trigeminal nucleus caudalis (TNC). It has been proposed that clinically effective 5-HT(1B/1D) agonists act peripherally to inhibit the release of calcitonin gene-related peptide (CGRP) and neurogenic dural vasodilation, and to attenuate nociceptive neurotransmission within the TNC. Since opioids are also effective anti-migraine agents the present studies investigated the role of opioids within the trigemino-vascular system in anaesthetised rats. Electrical stimulation of the dura mater evoked neurogenic dural vasodilation which was significantly inhibited by morphine (1 mg kg(-1)) the selective mu-opioid agonist DAGO (10 microg kg(-1)) and the mixed agonist/antagonist butorphanol (1 mg kg(-1)) but not by the kappa- and delta-opioid agonists (+/-) U50488H (100 microg kg(-1)) and DPDPE (1 mg kg(-1)). Morphine had no effect on CGRP-evoked dural vasodilation. In electrophysiological studies morphine (1 - 10 mg kg(-1)) significantly attenuated brainstem neuronal activity in response to electrical stimulation of the dura by 65% at 10 mg kg(-1). Morphine (3 mg kg(-1)) also inhibited the TNC neuronal sensitization following CGRP-evoked dilation. The present studies have demonstrated that opioids block the nociceptive neurotransmission within the trigeminal nucleus caudalis and in addition inhibit neurogenic dural vasodilation via an action on mu-opioid receptors located on trigeminal sensory fibres innervating dural blood vessels. These peripheral and central actions are similar to those of the 'triptan' 5-HT(1B/1D) agonists and could account for the anti-migraine actions of opioids.

MeSH terms

  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / pharmacology
  • Action Potentials / drug effects
  • Analgesics, Non-Narcotic / pharmacology
  • Analgesics, Opioid / pharmacology
  • Anesthesia
  • Animals
  • Blood Vessels / drug effects
  • Blood Vessels / physiology
  • Butorphanol / pharmacology
  • Calcitonin Gene-Related Peptide / pharmacology
  • Dose-Response Relationship, Drug
  • Dura Mater / blood supply
  • Dura Mater / drug effects
  • Dura Mater / physiology*
  • Electric Stimulation
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
  • Enkephalin, D-Penicillamine (2,5)- / pharmacology
  • Male
  • Morphine / pharmacology
  • Neurons / drug effects
  • Neurons / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid / physiology*
  • Trigeminal Caudal Nucleus / cytology
  • Trigeminal Caudal Nucleus / drug effects
  • Trigeminal Caudal Nucleus / physiology*
  • Vasodilation / drug effects
  • Vasodilation / physiology*


  • Analgesics, Non-Narcotic
  • Analgesics, Opioid
  • Receptors, Opioid
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
  • Morphine
  • Enkephalin, D-Penicillamine (2,5)-
  • Calcitonin Gene-Related Peptide
  • Butorphanol