dizocilpine-maleate and ketobemidone

There are clinical observations that neurogenic pain can respond well to the opioid ketobemidone, in contrast to pethidine and morphine. This has led us to the hypothesis that the analgesic effect of ketobemidone in neurogenic pain may be due to both opioid as well as additional non-opioid effects. The present study was therefore made to evaluate the effects of ketobemidone. The study consists of two parts. (1) Single unit recordings were made from dorsal horn neurones in the halothane-anaesthetised rat. Neurones were activated by transcutaneous electrical stimulation of their receptive fields at C-fibre strength and their responses quantified. The wind-up of the neurones, due to N-methyl-D-aspartate (NMDA) receptor activation, leading to marked increases in C-fibre responses and an associated post-discharge was also measured. Ketobemidone, applied to the spinal cord, equivalent to an intrathecal injection, dose-dependently and selectively reduced C-fibre evoked responses. Ketobemidone was also found to block wind-up more effectively than morphine at equieffective doses, but unlike morphine in a non-naloxone-reversible manner. (2) In a binding study ketobemidone was shown to inhibit [3H]MK-801 binding with a Ki value of 26 microM. Therefore, ketobemidone appears to possess both mu opioid agonist as well as NMDA blocking effects.

Topics: Analgesics, Opioid; Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electric Stimulation; Electrophysiology; Evoked Potentials; Injections, Spinal; Meperidine; Morphine; N-Methylaspartate; Nerve Fibers; Rats; Spinal Cord

The opiate agonists, ketobemidone, methadone and pethidine, were evaluated as N-methyl-D-aspartate (NMDA) receptor antagonists using the rat cortical wedge preparation and the neonatal rat spinal cord preparation for electrophysiological studies and [3H](RS)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-im ine ([3H]MK-801) binding experiments using rat forebrain homogenates. Ketobemidone, methadone and pethidine were inhibitors of [3H]MK-801 binding with Ki values of 26 microM, 0.85 microM and 47 microM, respectively. In the cortex, 1 mM ketobemidone and 1 mM methadone reduced NMDA responses, but not (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA) or kainate responses in an use-dependent manner, whereas 1 mM pethidine was devoid of antagonist activity. In the spinal cord preparation, the activities of ketobemidone and methadone were weaker than in cortex. In contrast, pethidine was equipotent with ketobemidone in the spinal cord. These results suggest that ketobemidone and methadone may be useful therapeutic agents in conditions where a combined opiate agonist and NMDA antagonist treatment is desired.

Topics: Analgesics, Opioid; Animals; Cerebral Cortex; Dizocilpine Maleate; Dose-Response Relationship, Drug; Meperidine; Methadone; Rats; Receptors, N-Methyl-D-Aspartate; Spinal Cord