The Analgesic Interaction Between Intrathecal Clonidine and Glutamate Receptor Antagonists on Thermal and Formalin-Induced Pain in Rats

Clonidine, an α2 adrenergic receptor agonist, inhibits glutamate release from the spinal cord. We studied the interaction of intrathecally administered clonidine and glutamate receptor antagonists on acute thermal or formalin induced nociception. Sprague-Dawley rats with lumbar intrathecal catheters were tested for their tail withdrawal response by the tail flick test and paw flinches produced by formalin injection after intrathecal administration of saline, clonidine, AP-5 (a N-methyl-D-aspartate receptor antagonist), or YM872 (an α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist). The combinations of clonidine and the other two agents were also tested by isobolographic analyses. Motor disturbance and behavioral changes were observed as side effects. The ED50 values of clonidine decreased from 0.26 μg (tail flick), 0.12 μg (Phase 1) and 0.13 μg (Phase 2) to 0.036 μg, 0.006 μg, and 0.013 μg with AP-5, and 0.039 μg, 0.057 μg, and 0.133 μg with YM872, respectively. Side effects were attenuated in both combinations. In conclusion, spinally administered clonidine and AP-5 or YM872 exhibited potent synergistic analgesia on acute thermal and formalin-induced nociception with decreased side effects in rats.