• R C Riley, J A Trafton, S I Chi, and A I Basbaum.
• Departments of Anatomy and Physiology and W. M. Keck Foundation Center for Integrative Neuroscience, University of California at San Francisco, San Francisco, CA 94143, USA.
• Neuroscience. 2001 Jan 1; 103 (3): 725-37.

AbstractInternalization of spinal cord neurokinin-1 receptors following noxious stimulation provides a reliable measure of tachykinin signaling. In the present study, we examined the contribution of GABAergic mechanisms to the control of nociceptor processing involving tachykinins. Spinal administration of the GABA(B) receptor agonist R(+)-baclofen in the rat, at antinociceptive doses, significantly reduced the magnitude of neurokinin-1 receptor internalization in neurons of lamina I in response to acute noxious mechanical or thermal stimulation. By contrast, administration of even high doses of the GABA(A) receptor agonists, muscimol or isoguvacine, were without effect. CGP55845, a selective GABA(B) receptor antagonist, completely blocked the effects of baclofen, but failed to increase the incidence of internalization when administered alone. These results provide evidence for a presynaptic control of nociceptive primary afferent neurons by GABA(B) but not GABA(A) receptors in the superficial laminae of the spinal cord, limiting tachykinin release. Because CGP5584 alone did not increase the magnitude of neurokinin-1 receptor internalization observed following noxious stimulation, there appears to be little endogenous activation of GABA(B) receptors on tachykinin-releasing nociceptors under acute stimulus conditions. The contribution of pre- and postsynaptic regulatory mechanisms to GABA(B) receptor-mediated antinociception was also investigated by comparing the effect of baclofen on Fos expression evoked by noxious stimulation to that induced by intrathecal injection of substance P. In both instances, baclofen reduced Fos expression not only in neurons that express the neurokinin-1 receptor, but also in neurons that do not. We conclude that baclofen acts at presynaptic sites to reduce transmitter release from small-diameter nociceptive afferents. Presynaptic actions on non-tachykinin-containing nociceptors could similarly account for the reduction by baclofen of noxious stimulus-induced Fos expression in neurokinin-1 receptor-negative neurons. However, the inhibition of Fos expression induced by exogenous substance P indicates that actions at sites postsynaptic to tachykinin- and/or non-tachykinin-containing primary afferent terminals must also contribute to the antinociceptive actions of GABA(B) receptor agonists.

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