The periaqueductal gray contributes to bidirectional enhancement of antinociception between morphine and cannabinoids

Pharmacol Biochem Behav. 2013 Jan;103(3):444-9. doi: 10.1016/j.pbb.2012.10.002. Epub 2012 Oct 10.


Co-administration of opioids and cannabinoids can enhance pain relief even when administered on different days. Repeated systemic administration of morphine has been shown to enhance the antinociceptive effect of tetrahydrocannabinol (THC) administered 12h later, and repeated microinjection of the cannabinoid receptor agonist HU-210 into the ventrolateral periaqueductal gray (PAG) has been shown to enhance the antinociceptive effect of morphine administered 1 day later. The primary objective of the present study was to test the hypothesis that this cannabinoid/opioid interaction is bidirectional. Experiment 1 showed that microinjection of morphine into the ventrolateral PAG of male Sprague-Dawley rats twice daily for 2 days enhanced the antinociceptive effect of HU-210 measured 1 day later. In Experiment 2, twice daily systemic injections of THC enhanced the antinociceptive effect of morphine administered 1 day later. These results complement the previously mentioned studies by showing that morphine and cannabinoid interactions are bidirectional and that the ventrolateral PAG plays an important role in this effect. In contrast to the PAG, repeated administration of HU-210 or the cannabinoid receptor agonist, WIN 55,212-2, into the RVM had a neurotoxic effect. Rats became ill following repeated cannabinoid administration whether given alone or with morphine. Presumably, this neurotoxic effect was caused by the high cannabinoid concentration following RVM microinjection because rats did not become ill following repeated systemic THC administration. These findings indicate that alternating opioid and cannabinoid treatment could produce a longer lasting and more potent analgesia than either compound given alone.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analgesics / administration & dosage
  • Analgesics / pharmacology*
  • Animals
  • Benzoxazines / administration & dosage
  • Benzoxazines / pharmacology
  • Dose-Response Relationship, Drug
  • Dronabinol / administration & dosage
  • Dronabinol / analogs & derivatives*
  • Dronabinol / pharmacology*
  • Drug Synergism
  • Injections, Subcutaneous
  • Male
  • Medulla Oblongata / drug effects
  • Microinjections
  • Morphine / administration & dosage
  • Morphine / pharmacology*
  • Morpholines / administration & dosage
  • Morpholines / pharmacology
  • Naphthalenes / administration & dosage
  • Naphthalenes / pharmacology
  • Pain Measurement / drug effects
  • Periaqueductal Gray / drug effects*
  • Periaqueductal Gray / physiology*
  • Rats
  • Rats, Sprague-Dawley


  • Analgesics
  • Benzoxazines
  • Morpholines
  • Naphthalenes
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • Morphine
  • Dronabinol
  • HU 211