Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance

Todd W Vanderah, Luis R. Gardell, Shannon E. Burgess, Mohab Ibrahim, Ahmet Dogrul, Cheng Min Zhong, En Tan Zhang, T. Philip Malan, Michael H. Ossipov, Josephine Lai, Frank Porreca

Research output: Contribution to journalArticle

259 Citations (Scopus)

Abstract

The nonopioid actions of spinal dynorphin may promote aspects of abnormal pain after nerve injury. Mechanistic similarities have been suggested between opioid tolerance and neuropathic pain. Here, the hypothesis that spinal dynorphin might mediate effects of sustained spinal opioids was explored. Possible abnormal pain and spinal antinociceptive tolerance were evaluated after intrathecal administration of [D-Ala2, N-Me-Phe4, Gly-ol5]enke phalin (DAMGO), an opioid μ agonist. Rats infused with DAMGO, but not saline, demonstrated tactile allodynia and thermal hyperalgesia of the hindpaws (during the DAMGO infusion) and a decrease in antinociceptive potency and efficacy of spinal opioids (tolerance), signs also characteristic of nerve injury. Spinal DAMGO elicited an increase in lumbar dynorphin content and a decrease in the μ receptor immunoreactivity in the spinal dorsal horn, signs also seen in the postnerve-injury state. Intrathecal administration of dynorphin A(1-17) antiserum blocked tactile allodynia and reversed thermal hyperalgesia to above baseline levels (i.e., antinociception). Spinal dynorphin antiserum, but not control serum, also reestablished the antinociceptive potency and efficacy of spinal morphine. Neither dynorphin antiserum nor control serum administration altered baseline non-noxious or noxious thresholds or affected the intrathecal morphine antinociceptive response in saline-infused rats. These data suggest that spinal dynorphin promotes abnormal pain and acts to reduce the antinociceptive efficacy of spinal opioids (i.e., tolerance). The data also identify a possible mechanism for previously unexplained clinical observations and offer a novel approach for the development of strategies that could improve the long-term use of opioids for pain.

Original languageEnglish (US)
Pages (from-to)7074-7079
Number of pages6
JournalJournal of Neuroscience
Volume20
Issue number18
StatePublished - Sep 15 2000

Fingerprint

Dynorphins
Opioid Analgesics
Hyperalgesia
Pain
Immune Sera
Neuralgia
Morphine
Wounds and Injuries
Serum

Keywords

  • μ-opioid receptors
  • Abnormal pain
  • Dynorphin
  • Dynorphin antiserum
  • Morphine tolerance
  • Spinal

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Vanderah, T. W., Gardell, L. R., Burgess, S. E., Ibrahim, M., Dogrul, A., Zhong, C. M., ... Porreca, F. (2000). Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance. Journal of Neuroscience, 20(18), 7074-7079.

Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance. / Vanderah, Todd W; Gardell, Luis R.; Burgess, Shannon E.; Ibrahim, Mohab; Dogrul, Ahmet; Zhong, Cheng Min; Zhang, En Tan; Malan, T. Philip; Ossipov, Michael H.; Lai, Josephine; Porreca, Frank.

In: Journal of Neuroscience, Vol. 20, No. 18, 15.09.2000, p. 7074-7079.

Research output: Contribution to journalArticle

Vanderah, TW, Gardell, LR, Burgess, SE, Ibrahim, M, Dogrul, A, Zhong, CM, Zhang, ET, Malan, TP, Ossipov, MH, Lai, J & Porreca, F 2000, 'Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance', Journal of Neuroscience, vol. 20, no. 18, pp. 7074-7079.
Vanderah TW, Gardell LR, Burgess SE, Ibrahim M, Dogrul A, Zhong CM et al. Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance. Journal of Neuroscience. 2000 Sep 15;20(18):7074-7079.
Vanderah, Todd W ; Gardell, Luis R. ; Burgess, Shannon E. ; Ibrahim, Mohab ; Dogrul, Ahmet ; Zhong, Cheng Min ; Zhang, En Tan ; Malan, T. Philip ; Ossipov, Michael H. ; Lai, Josephine ; Porreca, Frank. / Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance. In: Journal of Neuroscience. 2000 ; Vol. 20, No. 18. pp. 7074-7079.
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