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The Journal of Neuroscience, December 1, 1998, 18(23):9685-9694

Axotomy Reduces the Effect of Analgesic Opioids Yet Increases the Effect of Nociceptin on Dorsal Root Ganglion Neurons

Fuad A. Abdulla¹ and Peter A. Smith²

¹ Department of Physical Therapy, Tennessee State University, Nashville, Tennessee 37290, and ² Department of Pharmacology and Division of Neuroscience, University of Alberta, Edmonton, Alberta, Canada T6G 2H7

There is some doubt as to the effectiveness of opioids in the management of neuropathic pain. We therefore examined the actions of morphine and the opioid-like peptide nociceptin (both 1 µ) on dorsal root ganglion (DRG) neurons that were isolated from control or from nerve-injured rats. Both substances reduced -conotoxin (CTX) GVIA-sensitive, N-type Ca²⁺ channel current and small persistent nifedipine/ CTX-insensitive (non-N, non-L type) current. Nifedipine-sensitive L-type current was unaffected. The effect of nociceptin was antagonized by naloxone benzoylhydrazone (nalbzoh) but not by naloxone. Sciatic nerve section (axotomy) profoundly reduced the effects of morphine and the µ-receptor agonist D-ala², N-Me-Phe⁴,Gly-ol⁵ enkephalin (DAMGO). The effect of the -agonist [(+)-(5,7,8)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl)-benzeneacetamide] (U69593) was unchanged, whereas the effect of nociceptin was increased. All agonists produced their strongest effects on the small, putative nociceptive cells and their weakest effects on the largest cells. The -receptor agonist, enkephalin D-pen^2,5 (DPDPE), was without effect on control or on axotomized cells. These and other data suggest that the functional downregulation of µ-opioid receptors on sensory nerves contributes to the poor efficacy of opioids in neuropathic pain. Also, the increased effectiveness of nociceptin after axotomy supports the hypothesis that its actions are mediated via a "non-opioid" receptor. Pronounced suppression of Ca²⁺ channel current in axotomized DRG neurons by nociceptin led to a reduction in Ca²⁺-dependent K⁺ conductance and a marked increase in excitability. Despite this, the spinal administration of nociceptin or agonists that activate ORL₁ (opioid-like orphan receptor) may prove to be of clinical interest in the management of neuropathic pain.

Key words: sympathetic pain; spinal analgesia; substantia gelatinosa; superficial dorsal horn; C-fiber; causalgia; chronic constriction injury

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18239685-10$05.00/0

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