The mechanisms responsible for the pathological and behavioral changes that occur in the spinal cord of rats after sciatic nerve injury remain unclear. Great emphasis has been placed on the role of excitatory amino acids in the enhanced excitability of dorsal horn neurons and in the occurrence of neurotoxicity that leads to neuronal dysfunction after injury. Much less attention has been paid to the role of the inhibitory amino acid, gamma-aminobutyric acid (GABA). Yet, the spinal cord contains the highest concentration of GABA in the CNS. Moreover, GABA and GABAergic interneurons in the spinal cord play an important role in regulating afferent input to the spinal cord and in governing the excitability of dorsal horn neurons. This proposal will examine the role of GABA in the spinal cord in an animal model of neuropathic pain. These studies will use a multidisciplinary approach to determine whether the thermal hyperalgesia and tactile allodynia that result from peripheral nerve injury can be attributed to the loss of inhibitory mechanisms mediated by GABA in the dorsal horn. These studies will use in vitro autoradiography and immunocytochemistry to determine the alterations that occur in the distribution, density and affinity of spinal GABAA and GABAB receptors at various times after nerve injury. The function of these receptors will be established through intrathecal administration of GABAA and GABAB receptor antagonists and agonists at various times after nerve injury. Elucidation of the role of GABA in the development and maintenance of neuropathic pain may ultimately lead to the development of new therapeutic approaches to the management of neuropathic pain.
