Pronociceptive effects of spinal dynorphin promote cannabinoid-induced pain and antinociceptive tolerance

L. R. Gardell, S. E. Burgess, A. Dogrul, M. H. Ossipov, T. P. Malan, J. Lai, F. Porreca

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Recent studies indicate that sustained opioid administration produces increased expression of spinal dynorphin, which promotes enhanced sensitivity to non-noxious and noxious stimuli. Such increased 'pain' may manifest behaviorally as a decrease in spinal antinociceptive potency. Here, the possibility of similar mechanisms in the antinociception of spinal cannabinoids was explored. Response thresholds to non-noxious mechanical and noxious thermal stimuli were assessed. Antinociception was determined using the 52°C tail-flick test. Mice received repeated WIN 55,212-2, its inactive enantiomer, WIN 55,212-3 or vehicle (i.th., bid, 5 days). WIN 55,212-2, but not WIN 55,212-3 or vehicle, produced a time-related increased sensitivity to non-noxious and noxious stimuli. WIN 55,212-2, but not WIN 55,212-3 or vehicle, elicited a significant increase in lumbar spinal dynorphin content at treatment day 5. Increased sensitivity to mechanical and thermal stimuli produced by WIN 55,212-2 was reversed to baseline levels by i.th. MK-801 or dynorphin antiserum; control serum had no effect. WIN 55,212-2, but not WIN 55,212-3 or vehicle, produced dose-related antinociception and repeated administration resulted in antinociceptive tolerance. While MK-801 and dynorphin antiserum did not alter acute antinociception produced by WIN 55,212-2, these substances significantly blocked antinociceptive tolerance when given immediately prior to WIN 55,212-2 challenge on day 5. Daily MK-801 pretreatments, prior to WIN 55,212-2 injection, also produced a significant block of antinociceptive tolerance. These data suggest that like opioids, repeated spinal administration of a cannabinoid CB1 agonist elicits abnormal pain, which results in increased expression of spinal dynorphin. Manipulations that block cannabinoid-induced pain also block the behavioral manifestation of cannabinoid tolerance.

Original languageEnglish (US)
Pages (from-to)79-88
Number of pages10
JournalPain
Volume98
Issue number1-2
DOIs
StatePublished - Jul 15 2002

Keywords

  • Antinociceptive tolerance
  • Pain
  • Spinal dynorphin

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

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