Conditioned place aversion is a highly sensitive index of acute opioid dependence and withdrawal |
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Authors: | Marc?R?Azar Byron?C?Jones Email author" target="_blank">Gery?SchulteisEmail author |
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Institution: | (1) Department of Anesthesiology, UC San Diego School of Medicine and VA San Diego Healthcare System, 3350 La Jolla Village Drive, MC 125, San Diego, CA 92161-5085, USA;(2) Department of Biobehavioral Health, The Pennsylvania State University, 311 East Health and Human Development Building, University Park, PA 16802, USA;(3) Present address: Behavioral Pharma Inc., 665 San Rodolfo Drive, STE 124 PMB184, Solana Beach, CA 92075, USA |
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Abstract: | Rationale Conditioned place aversion (CPA) is known to be a sensitive measure of the aversive motivational state produced by opioid
withdrawal in rats made chronically dependent on opioids.
Objective The purpose of the present study was to examine the sensitivity of the CPA model in detecting a possible aversive state associated
with naloxone-precipitated withdrawal from acute treatment with morphine.
Methods Doses of morphine and naloxone, as well as number of conditioning trials, were systematically varied to determine the minimum
conditions that would result in a detectable CPA in male Wistar rats. Naloxone (0.003–16.7 mg/kg) was administered 4 h after
an injection of vehicle or morphine (1.0, 3.3, or 5.6 mg/kg) and immediately prior to confinement to one compartment of the
conditioning apparatus; rats received either one or two such naloxone-conditioning trials (separate by 48 h).
Results Morphine (5.6 mg/kg) followed 4 h later by vehicle produced no significant preference or aversion. In morphine-naive rats,
10 mg/kg naloxone was required to produce a significant CPA with two cycles of conditioning. When increasing doses of morphine
were administered (1.0, 3.3, 5.6 mg/kg), significant increases in naloxone potency to elicit a CPA were observed (16-, 211-,
and 1018-fold potency shifts, respectively). Naloxone potency after two pretreatments with 5.6 mg/kg morphine was comparable
to its potency to elicit a CPA after chronic exposure to morphine. Although naloxone was still effective in producing a CPA
after a single conditioning cycle (and hence a single morphine exposure), its effects were dramatically reduced relative to
those seen with two conditioning cycles.
Conclusions CPA is a reliable and sensitive index of the aversive motivational state accompanying withdrawal from acute opioid dependence. |
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Keywords: | Acute dependence Opioids Naloxone Conditioned place aversion Morphine |
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