Precipitated and conditioned withdrawal in morphine-treated rats.
BACKGROUND
Stimuli that are paired with opioid withdrawal can themselves produce effects similar to withdrawal that might promote relapse.


OBJECTIVE
This study compared precipitated and conditioned withdrawal and tested whether withdrawal is modified by clonidine or morphine.


METHODS
Morphine-treated rats (10 mg/kg/12 h) received naloxone (3.2 mg/kg) in a novel environment (conditioned stimuli [CS]). Other rats received naloxone in the absence of the CS. Body weight and observable signs were used to measure withdrawal.


RESULTS
Naloxone produced weight loss and withdrawal signs in morphine-treated rats. Following pairings of the CS and naloxone, the CS alone had effects similar to naloxone; conditioned withdrawal was greater after three naloxone/CS pairings, as compared to one, and with longer morphine treatment. Antagonist-precipitated withdrawal was greater in rats that previously were physically dependent on morphine, as compared to withdrawal in rats that were never dependent; however, conditioned withdrawal did not differ between groups. When administered concurrently with naloxone, clonidine (0.1 mg/kg) attenuated some precipitated withdrawal signs, although conditioned withdrawal was largely unchanged. Administration of 10 mg/kg of morphine before the CS alone attenuated all conditioned withdrawal signs, whereas 0.1 mg/kg of clonidine before the CS alone reduced some directly observable signs and not weight loss.


CONCLUSIONS
Conditioned withdrawal occurs rapidly and is greater with longer periods of morphine treatment or more pairings of naloxone and the CS; however, a history of physical dependence does not increase conditioned withdrawal. Modification of conditioned withdrawal by drugs might be a useful approach for treating relapse.
Becker
Ginger L
GL
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, Mail Code 7764, San Antonio, TX 78229, USA.
Gerak
Lisa R
LR
Li
Jun-Xu
JX
Koek
Wouter
W
France
Charles P
CP
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology; D003214:Conditioning, Classical / Q000187:drug effects; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000633:toxicity; D009021:Morphine Dependence / Q000150:complications*; D009270:Naloxone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*
D009292:Narcotic Antagonists; D009270:Naloxone; D009020:Morphine; D003000:Clonidine