A great deal of effort has been expended in attempting to define the role of
GABA in mediating the transmission and perception of
pain. Pursuit of this question has been stimulated by the fact that GABAergic neurons are widely distributed throughout the central nervous system, including regions of the spinal cord dorsal horn known to be important for transmitting
pain impulses to the brain. In addition, GABA neurons and receptors are found in supraspinal sites known to coordinate the perception and response to painful stimuli and this
neurotransmitter system has been shown to regulate control of sensory information processing in the spinal cord. The discovery that
GABA receptor agonists display antinociceptive properties in a variety of animal models of
pain has provided an impetus for developing such agents for this purpose. It has been shown that
GABA receptor agonists, as well as inhibitors of
GABA uptake or metabolism, are clinically effective in treating this symptom. However, even with an enhanced understanding of the relationship between GABAergic transmission and
pain, it has proven difficult to exploit these findings in designing novel
analgesics that can be employed for the routine management of
pain. Work in this area has revealed a host of reasons why GABAergic drugs have, to date, been of limited utility in the management of
pain. Chief among these are the side effects associated with such agents, in particular sedation. These limitations are likely due to the simultaneous activation of
GABA receptors throughout the neuraxis, most of which are not involved in the transmission or perception of
pain. This makes it difficult to fully exploit the antinociceptive properties of GABAergic drugs before untoward effects intervene. The discovery of molecularly and pharmacologically distinct GABAA receptors may open the way to developing subtype selective agents that target those receptors most intimately involved in the transmission and perception of
pain. The more limited repertoire of GABAB receptor subunits makes it more difficult to develop subtype selective agents for this site. Nonetheless, a GABAB agonist, CGP 35024, has been identified that induces antinociceptive responses at doses well below those that cause sedation (Patel et al., 2001). It has also been reported that, unlike
baclofen, tolerance to antinociceptive responses is not observed with
CGP 44532, a more potent GABAB receptor agonist (Enna et al., 1998). While the reasons for these differences in responses to members of the same class remain unknown, these findings suggest it may be possible to design a GABAB agonist with a superior clinical profile than existing agents. Besides the challenges associated with identifying subtype selective GABAA and GABAB receptor agonists, the development of
GABA analgesics has been hindered by the fact that the responsiveness of these receptor systems appear to vary with the type and duration of
pain being treated and the mode of
drug administration. Further studies are necessary to more precisely define the types of
pain most amenable to treatment with GABAergic drugs. Inasmuch as the antinociceptive responses to these agents in laboratory animals are mediated, at least in part, through activation or inhibition of other
neurotransmitter and
neuromodulator systems, it is conceivable that
GABA agonists will be most efficacious as
analgesics when administered in combination with other agents. The results of anatomical, biochemical, molecular, and pharmacological studies support the notion that generalized activation of
GABA receptor systems dampens the response to painful stimuli. The data leave little doubt that, under certain circumstances, stimulation of neuroanatomically discreet
GABA receptor sites could be of benefit in the management of
pain. Continued research in this area is warranted given the limited choices, and clinical difficulties, associated with conventional
analgesics.