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 chronically exposed to opiates, however, remain undefined. Using rats, each prepared with a spinal loop dialysis catheter and with a chronic lumbar intrathecal infusion catheter connected to a subcutaneous minipump, the release of amino acids before and during antagonist-precipitated withdrawal in unanesthetized rats was examined. Spinal infusion of morphine (20 nmol/micro l/hr) for 4 d had little effect on resting release of amino acids. In morphine-infused, but not saline-infused, rats naloxone (2 mg/kg, i.p.) evoked an immediate increase in the release of L-glutamate (299 +/- 143%) and taurine (306 +/- 113%) but not other amino 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 microg; alpha2 agonist), MK-801 (3 microg; noncompetitive NMDA antagonist), or aminophosphonopentanoic acid (AP-5; 3 microg; competitive NMDA antagonist) suppressed naloxone-induced increases in spinal L-glutamate and taurine release and behavioral signs of withdrawal in spinal morphine-infused rats. Results point to a correlated increase in spinal L-glutamate release, which contributes to genesis of the opioid withdrawal syndrome. Agents such as clonidine that suppress opioid withdrawal may owe their action to an inhibition of excitatory amino acid release. The effects of MK-801 and AP-5 suggest a glutamate-evoked glutamate release.
Jhamandas
K H
KH
Department of Anesthesia, University of California at San Diego, Ja Jolla 92093-0818, USA.
Marsala
M
M
Ibuki
T
T
Yaksh
T L
TL
D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D007278:Injections, Spinal; D008297:Male; D017551:Microdialysis; D009020:Morphine / Q000008:administration & dosage*; D009270:Naloxone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D013116:Spinal Cord / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D013654:Taurine / Q000378:metabolism; D013997:Time Factors
D000596:Amino Acids; D013654:Taurine; D009270:Naloxone; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D009020:Morphine; D003000:Clonidine; D005998:Glycine