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Mice were tested for antinociceptive activity after intrathecal injection of opioid or noradrenergic agonists by lumbar puncture. Opioid agonists with mu or delta activity and adrenergic agonists with alpha activity demonstrated dose-related, receptor-mediated analgesia in the tail-flick assay, s.c. hypertonic saline assay and the intrathecal substance P behavioral assay. Inhibition of substance P-induced biting and scratching by intrathecally administered antinociceptive agents is likely mediated by post-synaptic receptors. This action of opioids and norepinephrine was antagonized by their respective pharmacological antagonists. Subanalgesic doses of Leu-enkephalin or norepinephrine potentiated the antinociceptive activity of morphine in the substance P assay. Similarly, opioid agonists potentiated the action of norepinephrine. These results suggest that opioid and alpha adrenergic agonists act on separate …