Involvement of cannabinoid receptors in peripheral and spinal morphine analgesia

Neuroscience. 2014 Mar 7:261:23-42. doi: 10.1016/j.neuroscience.2013.12.030. Epub 2013 Dec 21.


The interactions between the cannabinoid and opioid systems for pain modulation are reciprocal. However, the role and the importance of the cannabinoid system in the antinociceptive effects of opioids remain uncertain. We studied these interactions with the goal of highlighting the involvement of the cannabinoid system in morphine-induced analgesia. In both phases of the formalin test, intra paw and intrathecal morphine produced similar antinociceptive effects in C57BL/6, cannabinoid type 1 and type 2 receptor wild-type (respectively cnr1WT and cnr2WT) mice. In cnr1 and cnr2 knockout (KO) mice, at the dose used the antinociceptive effect of intra paw morphine in the inflammatory phase of the formalin test was decreased by 87% and 76%, respectively. Similarly, the antinociceptive effect of 0.1μg spinal morphine in the inflammatory phase was abolished in cnr1KO mice and decreased by 90% in cnr2KO mice. Interestingly, the antinociceptive effect of morphine in the acute phase of the formalin test was only reduced in cnr1KO mice. Notably, systemic morphine administration produced similar analgesia in all genotypes, in both the formalin and the hot water immersion tail-flick tests. Because the pattern of expression of the mu opioid receptor (MOP), its binding properties and its G protein coupling remained unchanged across genotypes, it is unlikely that the loss of morphine analgesia in the cnr1KO and cnr2KO mice is the consequence of MOP malfunction or downregulation due to the absence of its heterodimerization with either the CB1 or the CB2 receptors, at least at the level of the spinal cord.

Keywords: cannabinoid receptors; formalin test; morphine; mu opioid receptors (MOP); pain; tail-flick test.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Edema / chemically induced
  • Edema / metabolism
  • Formaldehyde
  • Hindlimb / drug effects
  • Hindlimb / metabolism
  • Hot Temperature
  • Injections, Intradermal
  • Injections, Spinal
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Morphine / administration & dosage
  • Morphine / pharmacology*
  • Nociceptive Pain / drug therapy*
  • Nociceptive Pain / metabolism*
  • Pain Measurement
  • Receptor, Cannabinoid, CB1 / genetics
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Receptor, Cannabinoid, CB2 / genetics
  • Receptor, Cannabinoid, CB2 / metabolism*
  • Receptors, Opioid, mu / metabolism
  • Spinal Cord / metabolism


  • Analgesics, Opioid
  • CNR1 protein, mouse
  • Cnr2 protein, mouse
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Receptors, Opioid, mu
  • Formaldehyde
  • Morphine