MICROINJECTION OF BACLOFEN IN THE VENTROMEDIAL MEDULLA OF RATS - ANTINOCICEPTION AT LOW-DOSES AND HYPERALGESIA AT HIGH-DOSES

Neurons of the nucleus raphe magnus (NRM) and adjacent nucleus reticularis gigantocellularis pars alpha (NGCp alpha) receive a tonic inhibitory input from gamma-aminobutyric acid (GABA)-ergic neurons that is mediated by GABA(A) receptors. However, comparatively little is known about the role of GABA(B) receptors in these nuclei. The present study examined the effects on nociceptive threshold of microinjection of a wide dose range (0.1-150 ng) of the GABA(B) receptor agonist, baclofen hydrochloride (BAC), in the NRM, NGCp alpha or the nucleus reticularis gigantocellularis (NGC). Microinjection of low doses of R(+)-BAC (0.1-1.0 ng) in the NRM or the NGCp alpha, but not the NGC increased response latencies in the tail flick test. As the dose of BAC was increased to 30.0 to 50.0 ng, response latencies in the tail flick test diminished to control values. Microinjection of the highest dose, 150 ng, in either the NRM, NGCp alpha or NGC significantly decreased response latencies in the tail flick test. Response latencies in the hot plate test were not increased by microinjection of 0.1 to 5.0 ng of R(+)BAC in the NRM, NGCp alpha or NGC. Although hot plate latency was increased after microinjection of 30.0 to 50.0 ng of R(+)-BAC in these nuclei, the effect was confounded by the occurrence of motor dysfunction. The effects of BAC were stereospecific as nociceptive threshold and motor function were not altered by microinjection of either 0.5 ng or 150 no of the less active stereoisomer, S(-)-BAC. The biphasic effect of R(+)-BAC suggests the existence of multiple mechanisms by which GABA(B) receptors modulate the activity of neurons in the ventromedial medulla. It is proposed that the antinociception produced by low doses of R(+)-BAC results from disinhibition (activation) of neurons in the NRM and NGCp alpha as a consequence of the presynaptic inhibition of inhibitory GABAergic and/or noradrenergic inputs. The decrement in antinociceptive effect and hyperalgesia produced by higher doses of R(+)-BAC may result from a presynaptic inhibition of excitatory inputs to the NRM and NGCp alpha, postsynaptic hyperpolarization of neurons in these nuclei or the unmasking of a descending facilitatory pathway originating from the NRM, NGCp alpha and NGC.