Spinal GABAB receptors mediate antinociceptive actions of cholinergic agents in normal and diabetic rats

Spinally administered muscarinic receptor agonists or acetylcholinesterase inhibitors can produce antinociception. However, the mechanisms of the action of cholinergic agents in the spinal cord are not fully understood. Activation of spinal muscarinic receptors evokes gamma-aminobutyric acid (GABA) release, which reduces the glutamatergic synaptic input to dorsal horn neurons through GABA(B) receptors. In this study, we determined the functional role of spinal GABA(B) receptors in the antinociceptive action of intrathecal cholinergic agents in normal rats and in a rat model of diabetic neuropathic pain. Diabetes was induced by intraperitoneal streptozotocin in rats. The intrathecal catheter was inserted with its tip positioned at the lumbar spinal level. Nociceptive threshold was measured by the paw withdrawal latency in response to a radiant heat stimulus in normal rats. Mechanical allodynia in diabetic rats was determined by von Frey filaments applied to the hindpaw. The effect of intrathecal muscarine or neostigmine was examined through pretreatment with the specific GABA(B) receptor antagonist, CGP55845, or its vehicle. Intrathecal injection of muscarine or neostigmine significantly increased the withdrawal latency in response to a heat stimulus in normal rats and the withdrawal threshold in response to application of von Frey filaments in diabetic rats. Intrathecal pretreatment with CGP55845 significantly attenuated the effect of both muscarine or neostigmine in normal rats. Furthermore, the antiallodynic effect of intrathecal neostigmine and muscarine was largely eliminated by CGP55845 in diabetic rats. These data suggest that the GABA(B) receptors in the spinal cord mediate both the antinociceptive and antiallodynic actions of intrathecal muscarine or neostigmine in normal rats and in a rat model of diabetic neuropathic pain. This study provides new functional evidence that activation of spinal GABA(B) receptors is one of the important mechanisms underlying the antinociceptive action of intrathecal cholinergic agents.