Pergamon Pharmacology Biochemistry and Behavior,Vol.48, No. 1, pp. 1=8, 1994 Copyright ©1994Elsevier Science Ltd Printed in the USA.All fightsreserved 0091-3057/94 $6.00 + .oo Antagonist-Precipitated Opioid Withdrawal in Rats: Evidence for Dissociations Between Physical and Motivational Signs GUY A. HIGGINS I AND EDWARD M. SELLERS Addiction Research Foundation and Departments of Pharmacology and Medicine, University of Toronto, Toronto, Ontario, Canada Received 21 December 1992 HIGGINS, G. A. AND E. M. SELLERS. Antagonistprecipitated opioid withdrawalin rats: Evidence for dissociations betweenphysical and motivationalsigns. PHARMACOL BIOCHEM BEHAV 48(1) 1-8, 1994.-In rats made opioid de- pendant by the implantation of a single morphine 75 mg base pellet, an attempt was made to determine whether any correlation existed between physical and motivational withdrawal signs by adjusting the dose of naloxone used to precipitate withdrawal. The models used to study motivational signs were taste (one- and two-bottle) conditioning and operant responding for food under an FRI5 schedule of reinforcement. Naloxone at doses of 0.01 mg/kg and above produced both a conditioned taste aversion (two-bottle test only) and reduced food responding in morphine pellet, but not placebo pellet, implanted animals. No physical withdrawal signs, e.g., wet dog shakes, diarrhoea, were noted until naloxone doses of 0.05 mg/kg and above were used. It is concluded that the difference in naloxone doses required to elicit physical and motivational withdrawal components provides further support for their dissociation. Naloxone-precipitatedopioid withdrawal Taste conditioning Physical withdrawal signs Motivational withdrawal signs Operant responding Rat EARLY views that physical dependence served as the primary impetus for substance abuse behavior has been largely super- seded by an acknowledgement that the positive reinforcing properties of the abused drugs themselves serve a critical role in this process [e.g., see (20,37,38) for reviews]. Indeed, by implication, adaptive processes such as physical dependence are subsequent to chronic drug use and, therefore, offer no explanation as to why this behavior becomes established in the first place. Nevertheless, within certain drug classes, par- ticularly the opiates, the induction of physical dependence and consequent avoidance of an aversive withdrawal state, repre- sents one aspect of the motivational impetus maintaining drug self-administration behavior (18,37). It may be hypothesized then, that drugs that relieve withdrawal could serve as useful therapies for the treatment of substance, including opiate, abusers. Before attempting to identify such agents it is important to have some knowledge as to the clinical manifestations of a drug withdrawal state. Opioid withdrawal is characterized by a wide range of symptoms including nausea, gastrointestinal disturbance, various sympathomimetic reactions, agitation/ anxiety, and marked dysphoria (18,19,39). The time course and severity of these various symptoms are variable between patients and dependent on a variety of factors such as the particular drug, dally dosage, duration of use, environmental context, and method of withdrawal (i.e., spontaneous or an- tagonist-precipitated withdrawal) (18). However, irrespective of this, it seems to be a common observation that this phe- nomenon has profound behavioral, psychological, and physi- ological components. In preclinical research there has been a greater emphasis towards the delineation of these aspects of opioid withdrawal, for it seems that multiple systems are implicated. The peri- aqueductal grey and locus coeruleus appear to be particularly important for the expression of many physical opioid with- drawal signs (4,24,25) although other brain/spinal areas have been implicated (23-25) and a peripheral component may be responsible for secretory signs such as diarrhoea (23,25,27). s Requests for reprints should be addressed to Guy A. Higgins, Glaxo Unit of Behavioural Psychopharmacology, University of Hertfordshire, College Lane, Hatfield, Herts, UK.