Cannabinoid CB(2) receptor attenuates morphine-induced inflammatory responses in activated microglial cells

Br J Pharmacol. 2012 Aug;166(8):2371-85. doi: 10.1111/j.1476-5381.2012.01948.x.


Background and purpose: Among several pharmacological properties, analgesia is the most common feature shared by either opioid or cannabinoid systems. Cannabinoids and opioids are distinct drug classes that have been historically used separately or in combination to treat different pain states. In the present study, we characterized the signal transduction pathways mediated by cannabinoid CB(2) and µ-opioid receptors in quiescent and LPS-stimulated murine microglial cells.

Experimental approach: We examined the effects of µ-opioid and CB(2) receptor stimulation on phosphorylation of MAPKs and Akt and on IL-1β, TNF-α, IL-6 and NO production in primary mouse microglial cells.

Key results: Morphine enhanced release of the proinflammatory cytokines, IL-1β, TNF-α, IL-6, and of NO via µ-opioid receptor in activated microglial cells. In contrast, CB(2) receptor stimulation attenuated morphine-induced microglial proinflammatory mediator increases, interfering with morphine action by acting on the Akt-ERK1/2 signalling pathway.

Conclusions and implications: Because glial activation opposes opioid analgesia and enhances opioid tolerance and dependence, we suggest that CB(2) receptors, by inhibiting microglial activity, may be potential targets to increase clinical efficacy of opioids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cricetinae
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Gene Expression Regulation / drug effects
  • Humans
  • Indoles / pharmacology
  • Inflammation / metabolism*
  • Lipopolysaccharides
  • MAP Kinase Kinase 1 / genetics
  • MAP Kinase Kinase 1 / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Microglia / drug effects*
  • Microglia / metabolism
  • Morphine / pharmacology*
  • Naphthols
  • Nitric Oxide / metabolism
  • Nitrites / metabolism
  • RNA Interference
  • RNA, Small Interfering
  • Receptor, Cannabinoid, CB2 / genetics
  • Receptor, Cannabinoid, CB2 / metabolism*
  • Receptors, Opioid, mu / genetics
  • Receptors, Opioid, mu / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Triazines


  • 2-(3-aminophenol)-6-(4-amino-1-naphthol)-4-chloro-triazine
  • Cytokines
  • Indoles
  • Lipopolysaccharides
  • Naphthols
  • Nitrites
  • RNA, Small Interfering
  • Receptor, Cannabinoid, CB2
  • Receptors, Opioid, mu
  • Triazines
  • Nitric Oxide
  • Morphine
  • MAP Kinase Kinase 1
  • JHW 015