GABAergic modulation of descending inhibitory systems from the rostral ventromedial medulla (RVM). Dose-response analysis of nociception and neurological deficits.

We have examined the effects of muscimol and bicuculline microinjected in the rostral ventromedial medulla (RVM) on motor function and on nociception in three pain tests. In Exp. 1 microinjection of muscimol (6.25-400 ng in 1 microl) in the RVM dose-dependently decreased pain threshold of rats and the ED(50) for muscimol was the same in both the hot plate and tail immersion pain tests. In the hot plate test, but not in the tail immersion test, paw withdrawal latencies increased again with high doses of muscimol (75-400 ng). High doses also produced catalepsy. Exp. 2 examined the effects of muscimol (50 ng) and bicuculline (50 ng) over a range of formalin concentrations (0.25-4%) in the formalin test. Muscimol increased responsiveness to formalin and reduced the slope of the formalin dose-response relation. Bicuculline decreased responses to formalin and reduced the slope of the formalin dose-response relation. It is suggested that RVM cells with inhibitory projections to the dorsal horn are not subject to strong GABAergic influence under mild noxious stimulation. RVM cells are thus active, and spinal dorsal horn relay neurons are inhibited. On the other hand, intense noxious peripheral stimulation may stimulate the release of GABA onto RVM cells, which in turn shuts off descending inhibitory fibers to allow transmission of nociceptor input through the dorsal horn.