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Intrathecal morphine-3-glucuronide-induced nociceptive behavior via Delta-2 opioid receptors in the spinal cord

Takaaki Komatsu1, Soh Katsuyama2, Hiroshi Nagase3

  • 1Department of Pharmacology, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka, Fukuoka 815-8511, Japan; School of Pharmacy, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA.

Pharmacology, Biochemistry, and Behavior
|October 18, 2015
PubMed

Insights

Morphine metabolite M3G causes scratching via dynorphin conversion to leucine-enkephalin (Leu-ENK), activating delta-2 opioid receptors and spinal ERK. Leu-ENK, not dynorphin, mediates M3G

Area of Science:

  • Neuroscience
  • Pharmacology
  • Pain Research

Background:

  • Morphine-3-glucuronide (M3G), a major morphine metabolite, lacks analgesic properties but induces nociceptive behaviors.
  • The precise mechanisms underlying M3G-induced neurotoxicity and pain signaling remain incompletely understood.

Purpose of the Study:

  • To elucidate the opioid receptor subtypes and downstream signaling pathways involved in M3G-induced behavioral responses and spinal cord activation.
  • To investigate the role of dynorphin metabolism and leucine-enkephalin (Leu-ENK) in M3G-induced nociception.

Main Methods:

  • Intrathecal (i.t.) administration of M3G in mice, followed by behavioral assessments (scratching, biting, licking).
  • Pretreatment with antisera against dynorphin and Leu-ENK, and opioid receptor antagonists (nor-BNI, naltrindole, naltriben, BNTX).
  • Assessment of ERK activation in the lumbar dorsal spinal cord using Western blotting.

Main Results:

  • M3G induced dose-dependent scratching, inhibited by antisera against dynorphin and Leu-ENK, but not the kappa-opioid antagonist nor-BNI.
  • Leu-ENK-converting enzyme inhibitors potentiated M3G-induced responses.
  • Delta-2 opioid receptor antagonists (naltrindole, naltriben) inhibited M3G effects, while delta-1 antagonist (BNTX) did not.
  • M3G activated spinal ERK, an effect blocked by Leu-ENK and delta-2 opioid receptor antagonists.

Conclusions:

  • M3G-induced nociceptive responses and spinal ERK activation are mediated by Leu-ENK, derived from dynorphin.
  • These effects are triggered via the activation of delta-2 opioid receptors in the spinal cord.
Keywords:
Dorsal spinal cordDynorphinExtracellular signal-regulated kinase (ERK)Leucine-enkephalinMiceMorphine-3-glucuronide (M3G)δ(2)-opioid receptor

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