Role of NK-1 neurotransmission in opioid-induced hyperalgesia

Tamara King, Luis R. Gardell, Ruizhong Wang, Anna Vardanyan, Michael H. Ossipov, T. Philip Malan, Todd W. Vanderah, Stephen P. Hunt, Victor J. Hruby, Josephine Lai, Frank Porreca

Research output: Contribution to journalArticlepeer-review

146 Scopus citations


Opiates are among the most important drugs for treatment of moderate to severe pain and prolonged opiate administration is often required to treat chronic pain states. We investigated the neurobiological actions of sustained opiate administration revealing paradoxical pronociceptive adaptations associated with NK-1 receptor function. Sustained morphine delivered over 6 days elicited hyperalgesia in rats and mice during the period of opiate delivery. Sustained morphine administration increased substance P (SP) and NK-1 receptor expression in the spinal dorsal horn. Sustained morphine treatment also enhanced capsaicin-evoked SP release in vitro, and increased internalization of NK-1 receptors in response to noxious stimulation. While NK-1 receptor internalization was observed primarily in the superficial laminae of placebo-treated rats, NK-1 receptor internalization was seen in both superficial and deep lamina of the dorsal horn in morphine-treated animals. Morphine-induced hyperalgesia was reversed by spinal administration of an NK-1 receptor antagonist in rats and mice, and was observed in wildtype (NK-1 +/+), but not NK-1 receptor knockout (NK-1-/-), mice. These data support a critical role for the NK-1 receptor in the expression of sustained morphine-induced hyperalgesia. Additionally, these data indicate that sustained opiate administration induces changes reminiscent of those associated with inflammatory pain. These opiate-induced changes might produce unintended deleterious actions in the course of pain treatment in patients. Understanding of sustained morphine-induced neurochemical changes will help identify approaches that limit the deleterious actions of opiates.

Original languageEnglish (US)
Pages (from-to)276-288
Number of pages13
Issue number3
StatePublished - Aug 2005


  • Inflammatory pain
  • NK-1 receptor
  • Opioid-induced hyperalgesia
  • Substance P

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine


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