Opioid tolerance in periaqueductal gray neurons isolated from mice chronically treated with morphine

Br J Pharmacol. 2005 Sep;146(1):68-76. doi: 10.1038/sj.bjp.0706315.


The midbrain periaqueductal gray (PAG) is a major site of opioid analgesic action, and a significant site of cellular adaptations to chronic morphine treatment (CMT). We examined mu-opioid receptor (MOP) regulation of voltage-gated calcium channel currents (I(Ca)) and G-protein-activated K channel currents (GIRK) in PAG neurons from CMT mice. Mice were injected s.c. with 300 mg kg(-1) of morphine base in a slow release emulsion three times over 5 days, or with emulsion alone (vehicles). This protocol produced significant tolerance to the antinociceptive effects of morphine in a test of thermal nociception. Voltage clamp recordings were made of I(Ca) in acutely isolated PAG neurons and GIRK in PAG slices. The MOP agonist DAMGO (Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol enkephalin) inhibited I(Ca) in neurons from CMT mice (230 nM) with a similar potency to vehicle (150 nM), but with a reduced maximal effectiveness (37% inhibition in vehicle neurons, 27% in CMT neurons). Inhibition of I(Ca) by the GABA(B) agonist baclofen was not altered by CMT. Met-enkephalin-activated GIRK currents recorded in PAG slices were significantly smaller in neurons from CMT mice than vehicles, while GIRK currents activated by baclofen were unaltered. These data demonstrate that CMT-induced antinociceptive tolerance is accompanied by homologous reduction in the effectiveness of MOP agonists to inhibit I(Ca) and activate GIRK. Thus, a reduction in MOP number and/or functional coupling to G proteins accompanies the characteristic cellular adaptations to CMT previously described in PAG neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / pharmacology*
  • Animals
  • Baclofen / pharmacology
  • Calcium Channels / drug effects
  • Calcium Channels / physiology
  • Drug Tolerance / physiology*
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
  • GABA Agonists / pharmacology
  • Male
  • Membrane Potentials / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Morphine / pharmacology*
  • Neurons / drug effects
  • Neurons / physiology
  • Pain Measurement
  • Periaqueductal Gray / drug effects*
  • Periaqueductal Gray / metabolism
  • Periaqueductal Gray / physiology
  • Receptors, Opioid, mu / agonists*
  • Receptors, Opioid, mu / metabolism
  • Receptors, Opioid, mu / physiology


  • Analgesics, Opioid
  • Calcium Channels
  • GABA Agonists
  • Receptors, Opioid, mu
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Morphine
  • Baclofen