Activation of inhibition from the periaqueductal grey matter mediates central analgesic effect of metamizol (dipyrone).
The pyrazolone derivative, metamizol (dipyrone), possesses analgesic, antipyretic, anti-inflammatory and spasmolytic properties. It is often classified as peripherally acting. To test the possibility that a central action of the drug contributes to its antinociceptive and analgesic effects, experiments were carried out in which the tail-flick response to radiant heat, flexor reflex activity in the tibialis anterior muscle and activity in ascending spinal axons evoked by stimulation of afferent C fibres in the sural nerve, and activity of neurones in the periaqueductal grey matter and the substantia nigra were assessed in rats. Metamizol administered by intraperitoneal (i.p.; 10, 20 and 40 mg/kg) or intrathecal (i.t.; 50 to 400 micrograms) injection to intact rats dose-dependently prolonged the tail-flick latency. Administration by i.t. injection to spinal rats was without effect. Intravenous (i.v.) injection of metamizol (140 mg/kg) reduced flexor reflex activity in intact animals, while an i.t. injection to spinal rats was ineffective at a low dose (100 micrograms) or enhanced the reflex activity at a higher dose (400 micrograms). Activity in ascending axons responding to afferent C fibre stimulation was mostly depressed by i.t. injection of metamizol (40, 80 and 140 mg/kg) in rats with an intact spinal cord. Ascending activity was increased by i.t. injection of the drug (100 and 200 micrograms) to spinal rats. Metamizol (140 mg/kg) i.v. increased the activity of neurones in the PAG and reduced that of neurones in the substantia nigra. Metamizol administered by microinjection into the PAG prolonged the tail-flick latency (15-100 micrograms) and depressed C fibre-evoked activity in ascending axons (100 micrograms). The results suggest that a central action is involved in the analgesic effect of metamizol and that this central action manifests itself by an activation of inhibition originating in the PAG.
D000200:Action Potentials / Q000187:drug effects; D000632:Aminopyrine / Q000031:analogs & derivatives*; D000818:Animals; D004177:Dipyrone / Q000494:pharmacology*; D005260:Female; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009412:Nerve Fibers / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects*; D010146:Pain / Q000503:physiopathology*; D010147:Pain Measurement; D010487:Periaqueductal Gray / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D012018:Reflex / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects*; D013378:Substantia Nigra / Q000187:drug effects
D000632:Aminopyrine; D009270:Naloxone; D004177:Dipyrone; D009020:Morphine