GLUTAMATE SPINAL RETROGRADE SENSITIZATION OF PRIMARY SENSORY NEURONS ASSOCIATED WITH NOCICEPTION

In the present investigation we have tested the hypothesis that spinal glutamate release by inflammatory stimuli causes hyperalgesia through sensitization of the primary sensory neurons associated with nociception. In these experiments, the rat paw hyperalgesia pressure test in which inflammatory hyperalgesia is blocked by the intraplantar administration of morphine (MPH) or SNAP, a NO donor was used. Glutamate and glutamatergic ionotropic agonists such as NMDA or AMPA injected intrathecally (i.t.) caused a dose-dependent hyperalgesia. Quisqualate or ACPD, both of which are glutamate metabotropic receptor agonists, had no hyperalgesic effect. The hyperalgesic response to glutamate and NMDA injected i.t. was antagonized by the intraplantar (i.pl.) injection of either MPH or SNAP. This observation indicates that the hyperalgesia induced by glutamate acting through an NMDA pre-synaptic receptor causes sensitization of the primary sensory neurons. Confirming that the analgesia by i.pl; injection of SNAP or MPH was due to an action in primary peripheral sensory neurons, it was shown that pretreatment of the paws with methylene blue (MB, an inhibitor of guanylate cyclase) or with MB and L-NMMA (an inhibitor of NO synthase) abolished their respective analgesic effect. AMPA i.t. induced hyperalgesia was not inhibited by either i.pl. administration of MPH pr SNAP, indicating that its hyperalgesic capacity results from an action at a site other than the primary sensory neuron. Administration of the NMDA antagonists AP5 and MK801, but not the AMPA antagonist CNQX, inhibited the hyperalgesia induced by intraplantar injections of PGE, or carrageenin. Overall, our results indicate-that hyperalgesia evoked by an inflammatory stimulus in this model causes a continuous release of spinal glutamate which, via an NMDA-type receptor, promotes a retrograde sensitization of the primary sensory neurons.