Inhibiting a Spinal Dynorphin A Component Enhances Intrathecal Morphine Antinociception in Mice

Morphine given intracerebroventricularly releases spinal dynorphin A (Dyn) in mice. The present study was undertaken to determine whether morphine given intrathecally (IT) released Dyn. We demonstrated that the antinociceptive action of morphine was enhanced by procedures that are known to attenuate Dyn action. First, coadministration of the opiate antagonists, naloxone (5 fg), norbinaltorphimine (5 fg) or β-funaltrexamine (0.25 ng) with IT morphine (0.15 μg, 5 min) increased antinociceptive percentage maximum possible effect (%MPE) from 30% to 65%. Second, dynorphin antiserum (5 μg, 1 h, IT), which neutralizes Dyn action, enhanced morphine (0.2 μg, 5 min, IT) action; MPE of 27% was increased to 60%. Third, production of desensitization to the antagonistic action of Dyn, IT, by pretreatment with morphine [10 mg/kg, 3 h, subcutaneously (SC)], or 2 μg, 3 h, IT) or Dyn (1 ng, 1 h, IT) increased the 30% MPE of IT morphine to 60%. Naloxone [1 ng/kg, intraperitoneally (IP)] enhanced IT morphine at a peak time of 20 min. Nalmefene [1 to 100 ng/kg, per os (PO)] enhanced IT morphine action. In conclusion, the present study showed that IT morphine putatively released spinal Dyn.