Competitive and non-competitive NMDA antagonists block the development of antinociceptive tolerance to morphine, but not to selective μ or δ opioid agonists in mice

Edward J. Bilsky, Charles E. Inturrisi, Wolfgang Sadée, Victor J Hruby, Frank Porreca

Research output: Contribution to journalArticle

98 Citations (Scopus)

Abstract

N-Methyl-D-aspartate (NMDA) receptor antagonists have been shown to block the development of antinociceptive tolerance to morphine. Assessment of the effects of NMDA antagonists on development of antinociceptive tolerance to selective opioid mu (μ) and delta (δ) agonists, however, has not been reported. In these experiments, selective μ and δ receptor agonists, and morphine, were repeatedly administered to mice either supraspinally (i.c.v.) or systemically (s.c.), alone or after pretreatment with systemic NMDA antagonists. Antinociception was evaluated using a warm-water tail-flick test. Repeated i.c.v. injections of μ agonists including morphine, fentanyl, [D-Ala2, NMePhe4, Gly-ol]enkephalin (DAMGO) and Tyr-Pro-NMePhe-D-Pro-NH2 (PL017) or [D-Ala2, Glu4]deltorphin, a δ agonist, or s.c. injections of morphine or fentanyl, produced antinociceptive tolerance as shown by a significant rightward displacement of the agonist dose-response curves compared to controls. Single injections or repeated administration of MK801 (a non-competitive NMDA antagonist) or LY235959 (a competitive NMDA antagonist) at the doses employed in this study did not produce behavioral toxicity, antinociception or alter the acute antinociceptive effects of the tested opioid agonists. Consistent with previous reports, pretreatment with MK801 or LY235959 (30 min prior to agonist administration throughout the tolerance regimen) prevented the development of antinociceptive tolerance to i.c.v. or s.c. morphine. Neither NMDA antagonist, however, affected the development of antinociceptive tolerance to i.c.v. fentanyl, DAMGO, or [D-Ala2, Glu4]deltorphin. Additionally, MK801 pretreatment did not affect the development of antinociceptive tolerance to i.c.v. PL017 or to s.c. fentanyl. Further, MK801 pretreatment also did not affect the development of tolerance to the antinociception resulting from a cold-water swim-stress episode, previously shown to be a δ-opioid mediated effect. These data lead to the suggestion that the mechanisms of tolerance to receptor selective μ and δ opioids may be regulated differently from those associated with morphine. Additionally, these findings emphasize that conclusions reached with studies employing morphine cannot always be extended to 'opiates' in general.

Original languageEnglish (US)
Pages (from-to)229-237
Number of pages9
JournalPain
Volume68
Issue number2-3
DOIs
StatePublished - Dec 1996

Fingerprint

N-Methylaspartate
Morphine
Opioid Analgesics
Fentanyl
LY 235959
Injections
tyrosyl-proline
Opiate Alkaloids
mu Opioid Receptor
Opioid Receptors
N-Methyl-D-Aspartate Receptors
Dehydration
Tail
Water

Keywords

  • δ receptors
  • μ receptors
  • antinociceptive tolerance
  • LY235959
  • mice
  • MK801
  • N-methyl-D-aspartate antagonists
  • opioids
  • swim-stress

ASJC Scopus subject areas

  • Clinical Neurology
  • Psychiatry and Mental health
  • Neurology
  • Neuroscience(all)
  • Pharmacology
  • Clinical Psychology

Cite this

Competitive and non-competitive NMDA antagonists block the development of antinociceptive tolerance to morphine, but not to selective μ or δ opioid agonists in mice. / Bilsky, Edward J.; Inturrisi, Charles E.; Sadée, Wolfgang; Hruby, Victor J; Porreca, Frank.

In: Pain, Vol. 68, No. 2-3, 12.1996, p. 229-237.

Research output: Contribution to journalArticle

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