Dynorphin promotes opioid-induced abnormal pain and antinociceptive tolerance

Abstract

Consequences of injury to peripheral nerves and opioid tolerance share features including tactile and thermal hypersensitivity, decreased spinal opioid antinociception and upregulation of spinal dynorphin. Dynorphin may normally produce antinociception (opioid effect) but may be pronociceptive in pathological states (through direct or indirect actions at NMDA receptors). Sustained morphine, but not placebo, exposure elicited a time-related onset of both tactile and thermal hypersensitivity along with antinociceptive tolerance to i.th. morphine. Spinal dynorphin levels were significantly increased following morphine exposure. Treatment with either i.th. MK-801 or antiserum to dynorphin (Dyn A/S) reversed both morphine-induced abnormal pain and antinociceptive tolerance to spinal morphine. Control pre-immune control serum had no effect. Sustained administration of either DAMGO or (-)-oxymorphone (active form), but not (+)-oxymorphone (inactive form) or vehicle, produced both tactile and thermal hypersensitivity along with antinociceptive tolerance to i.th. agonist challenge. Spinal dynorphin levels were significantly increased following treatment with either DAMGO or (-)-oxymorphone. The possibility that 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, day after subcutaneous morphine pellet implantation; placebo pellets produced no effects. Basal and capsaicin-evoked release of CGRP was measured in minced spinal cord tissues taken from naive rats or from rats on post-pellet days 1 and 7. The content and evoked release of CGRP was significantly increased in tissues from morphine-exposed rats at 7, but not 1, day after implantation. Prodynorphin "knock-out" (KO) and wild-type (WT) mice were studied for changes in sensitivity to non-noxious mechanical and noxious radiant heat after morphine or placebo pellet. After 5 days of treatment, WT, but not KO, mice developed antinociceptive tolerance. Morphine, but not placebo pellet produced a time-related increased sensitivity to non-noxious and noxious stimuli in WT, but not in KO, mice. These data suggest that sustained morphine induces plasticity in both primary afferents and the spinal cord, including increased CGRP and dynorphin content. Morphine-induced elevation of spinal dynorphin content depends on descending influences and enhances stimulated CGRP release. (Abstract shortened by UMI.)