normorphine and Pain

Topics: Humans; Kidney Diseases; Morphine Derivatives; Myoclonus; Pain

A series of novel 1'-methylxanthene-9-spiro-4'-piperidines has been prepared in the search for opiate analgesics with improved pharmacological properties. It has been found that introduction of a hydroxyl group into the 4-position of the xanthenespiropiperidine nucleus produces a potent mu-opiate agonist. The structure-activity relationship of the series has been explored by use of isosteric replacements of the phenolic hydroxyl group. Moreover, the effect of altering the conformation of the piperidine ring has been studied. It was interesting to note that, in compounds lacking the phenolic hydroxyl group, opiate activity could be produced by introduction of the (phenylamino)ethyl group instead of methyl at the 1'-position.

Topics: Analgesics, Opioid; Animals; Guinea Pigs; Ileum; In Vitro Techniques; Mice; Molecular Structure; Muscle Contraction; Muscle, Smooth; Pain; Piperidines; Structure-Activity Relationship; Xanthines

The profound and prolonged effects of morphine in patients with renal dysfunction have been associated with high plasma levels of the opiate metabolites morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) rather than an increased concentration of morphine. We present here electrophysiological evidence to suggest that potent spinal antinociception can be produced by both M6G and normorphine, another metabolite of morphine. Extracellular recordings of A beta- and C-fibre-evoked responses of convergent dorsal horn neurones were made in the halothane anaesthetised rat. M6G elicited dose-dependent, naloxone-reversible inhibitions of C-fibre-evoked responses which were completely suppressed (8% of control) by 2 micrograms M6G whereas A beta-fibre-evoked responses were only reduced to 57% of controls. The ED50 for the effects of M6G on C-fibre-evoked activity was calculated to be 0.53 micrograms. Systemic administration of M6G (2 mg/kg) also profoundly reduced noxious evoked neuronal activity. Intrathecal normorphine was less potent than M6G but complete selective inhibitions of C-fibre-evoked response could be elicited by 25 micrograms and the ED50 was calculated to be 2.68 micrograms. No such inhibitions were observed following administration of M3G. A comparison with intrathecal morphine in the same preparation reveals that normorphine is equipotent with morphine whereas M6G is 13-fold more potent. These results therefore confirm that M6G and normorphine might be significant contributers to opiate analgesia after administration of morphine.

Topics: Action Potentials; Animals; Dose-Response Relationship, Drug; Male; Morphine; Morphine Derivatives; Nociceptors; Pain; Rats; Rats, Inbred Strains; Spinal Cord