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Tolerance and sensitization to chronic escalating dose heroin following extended withdrawal in Fischer rats: possible role of mu-opioid receptors

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Abstract

Rationale/objectives

Heroin addiction is characterized by recurrent cycles of drug use, abstinence, and relapse. It is likely that neurobiological changes during chronic heroin exposure persist across withdrawal and impact behavioral responses to re-exposure. We hypothesized that, after extended withdrawal, heroin-withdrawn rats would express behavioral tolerance and/or sensitization in response to heroin re-exposure and that these responses might be associated with altered mu-opioid receptor (MOPr) activity.

Methods

Male Fischer rats were exposed chronically to escalating doses of heroin (7.5–75 mg/kg/day), experienced acute spontaneous withdrawal and extended (10-day) abstinence, and were re-exposed chronically to heroin. Homecage behaviors and locomotor activity in response to heroin, as well as somatic withdrawal signs, were recorded. Separate groups of rats were sacrificed after extended abstinence and MOPr expression and G-protein coupling were analyzed using [3H]DAMGO and [35S]GTPγS assays.

Results

The depth of behavioral stupor was lower during the initial days of heroin re-exposure compared to the initial days of the first exposure period. Behavioral responses (e.g., stereotypy) and locomotion were elevated in response to heroin re-exposure at low doses. Rats conditioned for heroin place preference during the chronic re-exposure period expressed heroin preference during acute withdrawal; this preference was stronger than rats conditioned during chronic heroin exposure that followed chronic saline and injection-free periods. Extended withdrawal was associated with increased MOPr expression in the caudate-putamen and frontal and cingulate cortices. No changes in G-protein coupling were identified.

Conclusions

Aspects of tolerance/sensitization to heroin are present even after extended abstinence and may be associated with altered MOPr density.

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Acknowledgments

This research was supported by NIH-NIDA P60-DA05130-25 to M.J.K., and the Dorothea Dix Postdoctoral Fellowship and NIH-NIDA 5F32-DA030831-02 to K.M.S-C. Diacetylmorphine hydrochloride was generously provided by the NIH-NIDA Division of Drug Supply and Analytical Services. The authors have no conflicts of interest, financial or otherwise, pertaining to any aspect of the work reported in this manuscript. All experiments described herein comply with the current laws of the country in which they were performed. The authors thank Drs. Ellen Unterwald and Alexis Bailey for their advice on imaging analyses and protocols.

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  1. Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA

    Katharine M. Seip-Cammack, Brian Reed, Yong Zhang, Ann Ho & Mary Jeanne Kreek

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Correspondence to Katharine M. Seip-Cammack.

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Seip-Cammack, K.M., Reed, B., Zhang, Y. et al. Tolerance and sensitization to chronic escalating dose heroin following extended withdrawal in Fischer rats: possible role of mu-opioid receptors. Psychopharmacology 225, 127–140 (2013). https://doi.org/10.1007/s00213-012-2801-2

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