Relationship between the antinociceptive response to desipramine and changes in GABA B receptor function and subunit expression in the dorsal horn of the rat spinal cord

Abstract

Although tricyclic antidepressants are among the drugs of choice for the treatment of neuropathic pain, their mechanism of action in this regard remains unknown. Because previous reports suggest these agents may influence γ-aminobutyric acid (GABA) neurotransmission, and GABA B receptors are known to participate in the transmission of pain impulses, the present experiments were undertaken to examine whether the administration of desipramine alters GABA B receptor subunit expression and function in the dorsal horn of the rat spinal cord. For the study, rats were injected (i.p.) once daily with desipramine (15 mg/kg) for 7 consecutive days, during which their thermal withdrawal threshold was monitored, and after which GABA B receptor function, and the levels of GABA B receptor subunit mRNA, were quantified in the spinal cord dorsal horn. The results indicate that 4–7 days of continuous administration of desipramine are necessary to observe a significant increase in the thermal pain threshold. Moreover, it was found that 7 days of treatment with desipramine enhances GABA B receptor function, as measured by baclofen-stimulated [ 35 S ]GTPγS binding, and increases mRNA expression for the GABA B(1a) and GABA B(2), but not GABA B(1b), subunits. These findings suggest the antinociceptive effect of desipramine is accompanied by a change in spinal cord GABA B receptor sensitivity that could be an important component in the analgesic response to this agent.