The analgesic interaction between intrathecal clonidine and glutamate receptor antagonists on thermal and formalin-induced pain in rats

Clonidine, an alpha (2) adrenergic receptor agonist, inhibits glutamate rel ease from the spinal cord. We studied the interaction of intrathecally admi nistered clonidine and glutamate receptor antagonists on acute thermal or f ormalin induced nociception. Sprague-Dawley rats with lumbar intrathecal ca theters were tested for their tail withdrawal response by the tail flick te st and paw flinches produced by formalin injection after intrathecal admini stration of saline, clonidine, AP-5 (a N-methyl-D-aspartate receptor antago nist), or YM872 (an alpha -amino-3-hydroxy-5-methylisoxazole-4-propionic ad d receptor antagonist). The combinations of clonidine and the other two age nts were also tested by isobolographic analyses. Motor disturbance and beha vioral changes were observed as side effects. The ED50 values of clonidine decreased from 0.26 mug (tail flick), 0.12 mug (Phase 1) and 0.13 mug (Phas e 2) to 0.036 mug, 0.006 mug, and 0.013 mug with AP-5, and 0.039 mug, 0.057 mug, and 0.133 mug with YM872, respectively. Side effects were attenuated in both combinations. In conclusion, spinally administered clonidine and AP -5 or MM872 exhibited potent synergistic analgesia on acute thermal and for malin-induced nociception with decreased side effects in rats.