Putative role of medullary off- and on-cells in the antinociception produced by dipyrone (metamizol) administered systemically or microinjected into PAG

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Abstract
Recent investigations have shown that non-steroidal antiinflammatory drugs (NSAIDs) may exert an antinociceptive effect when administered at or within the central nervous system (CNS). This might be due to the engagement of CNS substrates that support the analgesic effects of opiates, including the periaqueductal gray matter (PAG) and the rostral ventromedial medulla (RVM). The off- and on-cells of the RVM have been proposed to inhibit and facilitate, respectively, nociceptive transmission. Accordingly, upon heating of a rat's tail the tail-flick (TF) reflex occurs only after off-cells have decreased, and on-cells have increased, their activity. In the present study, i.v. administration (200 and 400 mg/kg) or PAG microinjection (25, 50, 100 and 250 micrograms) of dipyrone (metamizol) to lightly anesthetized rats caused a dose-related retardation of the heat-elicited off-cell pause, on-cell discharge and corresponding TF. Neuronal response and TF retained their mutual time relationship but shifted pari passu toward longer latencies. This antinociception was apparent already 5 min post-injection and reached a maximum in 50-60 min for i.v. administration and 30-35 min for PAG microinjection. These results confirm other authors' findings of the direct antinociceptive action of NSAIDs upon PAG, and provide the first evidence for a plausible involvement of RVM off- and on-cells in such antinociceptive effect.