SPINAL AMINO-ACID RELEASE AND PRECIPITATED WITHDRAWAL IN RATS CHRONICALLY INFUSED WITH SPINAL MORPHINE

Glutamate receptors are implicated in the genesis of opioid tolerance and dependence. Factors governing release of amino acids in systems ch ronically exposed to opiates, however, remain undefined. Using rats, e ach prepared with a spinal loop dialysis catheter and with a chronic l umbar intrathecal infusion catheter connected to a subcutaneous minipu mp, the release of amino acids before and during antagonist-precipitat ed withdrawal in unanesthetized rats was examined. Spinal infusion of morphine (20 nmol/mu l/hr) for 4 d had little effect on resting releas e of amino acids. In morphine-infused, but not saline-infused, rats na loxone (2 mg/kg, i.p.) evoked an immediate increase in the release of L-glutamate (299 +/- 143%) and taurine (306 +/- 113%) but not other am ino acids. The magnitude and time course of the release of these amino acids significantly correlated with behavioral indices of withdrawal intensity. Acute intrathecal pretreatment immediately before naloxone with clonidine (20 mu g; alpha 2 agonist), MK-801 (3 mu g; noncompetit ive NMDA antagonist), or aminophosphonopentanoic acid (AP-5; 3 mu g; c ompetitive NMDA antagonist) suppressed naloxone-induced increases in s pinal L-glutamate and taurine release and behavioral signs of withdraw al in spinal morphine-infused rats. Results point to a correlated incr ease in spinal L-glutamate release, which contributes to genesis of th e opioid withdrawal syndrome. Agents such as clonidine that suppress o pioid withdrawal may owe their action to an inhibition of excitatory a mino acid release. The effects of MK-801 and AP-5 suggest a glutamate- evoked glutamate release.