A Nonopioid Analgesic Acts Upon the PAG-RVM Axis to Reverse Inflammatory Hyperalgesia

Metamizol (dipyrone) and other nonsteroidal anti-inflammatory drugs (NSAIDs) induce antinociception by acting upon peripheral tissues and upon central nervous system structures, notably the periaqueductal grey matter (PAG) and the spinal cord. Inflammation-induced hyperalgesia is prevented by spinal application of NSAIDs before the inflammation, but once central sensitization is established the spinal effect of NSAIDs is uncertain. The present study examines whether the action upon the PAG contributes to the attenuation of inflammation-induced spinal hyperalgesia by NSAIDs. In deeply anaesthetized rats, responses of spinal multireceptive neurons to mechanical stimulation of the ipsilateral paw and leg were recorded. An inflammation in the paw was induced with carrageenan. Fifty minutes later, neuronal responses to innocuous and noxious stimulation had, respectively, increased to 206 and 304% for paw, and 160 and 190% for leg. When metamizol (150 microg in 0.5 microL) was microinjected into PAG before the inflammation, neuronal hyperexcitability was delayed for approximately 60 min and was much reduced by 215 min. More interestingly, microinjection of metamizol into PAG when hyperexcitability was fully developed depressed neuronal responses down to baseline for approximately 1 h. The effect of PAG metamizol was reversed by microinjection of a GABA(A) agonist into the rostral ventromedial medulla (RVM), which indicates that RVM relays the metamizol effect from PAG onto the spinal cord. These results suggest that, upon clinical administration of NSAIDs, a joint action upon PAG and spinal cord contributes to preventing the development of hyperalgesia but it is mainly the action upon PAG which contributes to reducing fully established hyperalgesia.