Sustained morphine exposure induces a spinal dynorphin-dependent enhancement of excitatory transmitter release from primary afferent fibers

Luis R. Gardell, Ruizhong Wang, Shannon E. Burgess, Michael H. Ossipov, Todd W. Vanderah, T. Philip Malan, Josephine Lai, Frank Porreca

Research output: Contribution to journalArticlepeer-review

208 Scopus citations


Paradoxical opioid-induced pain has been demonstrated repeatedly in humans and animals. The mechanisms of such pain are unknown but may relate to opioid-induced activation of descending pain facilitatory systems and enhanced expression and pronociceptive actions of spinal dynorphin, Here, the possibility that these opioid-induced central changes might mediate increased excitability to the spinal cord was tested. Tactile and thermal hypersensitivity was observed at 7, but not 1, days after subcutaneous morphine pellet implantation; placebo pellets produced no effects, Basal and capsaicin-evoked release of calcitonin gene-related peptide (CGRP) was measured in minced spinal tissues taken from naive rats or rats on post-pellet days 1 and 7, The content and evoked release of CGRP were significantly increased in tissues from morphine-exposed rats at 7, but not 1, days after implantation. Morphine increased spinal dynorphin content on day 7 in rats with sham bilateral lesions of the dorsolateral funiculus (DLF) but not in rats with DLF lesions. Pharmacological application of dynorphin A(2-13), a non-opioid fragment, to tissues from naive rats enhanced the evoked release of CGRR Enhanced evoked release of CGRP from morphine-pelleted rats was blocked by dynorphin anti-serum or by previous lesions of the DLF. Sustained morphine induces plasticity in both primary afferents and spinal cord, including increased CGRP and dynorphin content. Morphine-induced elevation of spinal dynorphin content depends on descending influences and enhances stimulated CGRP release. Enhanced transmitter release may allow increased stimulus-evoked spinal excitation, which is likely to be critical for opioid-induced paradoxical pain. Such pain may manifest behaviorally as antinociceptive tolerance.

Original languageEnglish (US)
Pages (from-to)6747-6755
Number of pages9
JournalJournal of Neuroscience
Issue number15
StatePublished - Aug 1 2002


  • CGRP release
  • Descending facilitation
  • Opiate tolerance
  • Opioid paradoxical pain
  • Opioid trophic effects
  • Spinal dynorphin

ASJC Scopus subject areas

  • Neuroscience(all)


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