Intrathecal clonidine: analgesia and effect on opiate withdrawal in the rat

Clonidine, an alpha 2 adrenergic agonist, has analgesic properties and recently has been used to suppress opiate withdrawal. These two properties theoretically make it a suitable analgesic substitute in patients tolerant to opioids. The objectives of this study were to see if intrathecal clonidine is analgesic and whether it can modify morphine withdrawal at the spinal level. Rats chronically implanted with catheters in the lumbar subarachnoid space were utilized. In analgesia experiments, intrathecal clonidine produced analgesia with the peak effect in the paw-lick test occurring at 200nM, and in the tail-flick test analgesia was apparent at 100 nM and peaked at 400 nM (in 10 microL Ringer's lactate). In dependency experiments, animals dependent on morphine (300 mg X kg-1) received intrathecal clonidine 25, 50, 200 nM in 10 microliter Ringer's lactate 72 h after morphine. Following this, a naloxone challenge, 3 mg X kg-1 was administered and withdrawal assessed. Clonidine-treated animals showed significant weight loss and decrease in temperature, and those treated with high doses showed marked hypothermia and hind-limb flaccidity. Intrathecal clonidine prevented the hyperalgesia associated with opiate withdrawal but did not affect the occurrence of the majority of behavioral signs (e.g., piloerection, irritability) associated with morphine withdrawal. Intrathecal clonidine prevented the naloxone-induced increase in blood pressure during withdrawal and in animals not treated with morphine-produced hypotension. Thus, intrathecal clonidine is analgesic, and part of the antiwithdrawal action of clonidine may be exerted at the spinal level.