Abstract
Chronic pain can be a debilitating condition, leading to profound changes in nearly every aspect of life. However, the reliance on opioids such as oxycodone for pain management is thought to initiate dependence and addiction liability. The neurobiological intersection at which opioids relieve pain and possibly transition to addiction is poorly understood. Using RNA sequencing pathway analysis in rats with complete Freund’s adjuvant (CFA)-induced chronic inflammation, we found that the transcriptional signatures in the medial prefrontal cortex (mPFC; a brain region where pain and reward signals integrate) elicited by CFA in combination with oxycodone differed from those elicited by CFA or oxycodone alone. However, the expression of Egr3 was augmented in all animals receiving oxycodone. Furthermore, virus-mediated overexpression of EGR3 in the mPFC increased mechanical pain relief but not the affective aspect of pain in animals receiving oxycodone, whereas pharmacological inhibition of EGR3 via NFAT attenuated mechanical pain relief. Egr3 overexpression also increased the motivation to obtain oxycodone infusions in a progressive ratio test without altering the acquisition or maintenance of oxycodone self-administration. Taken together, these data suggest that EGR3 in the mPFC is at the intersection of nociceptive and addictive-like behaviors.
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The datasets generated during and/or analyzed during the present study are available from the corresponding author on reasonable request.
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Acknowledgements
The NIDA Drug Supply Program generously gifted the oxycodone used in these studies. We thank Karen Dietz for copy editing the manuscript. We also thank Jacob Converse and Mason Hochstetler for their support in conducting experiments.
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This work was supported by the National Institute on Drug Abuse (NIDA; R01DA037257, S1-R01DA037257, and R21DA044486 to D.M.D.), National Institute of Neurological Disorders and Stroke (NINDS; F99NS108543 to J.A.S.), and National Institute of General Medical Sciences (NIGMS; R25GM09545902 to The State University of New York at Buffalo).
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S.M., S.A.T., J.A.S., J.X.L., and D.M.D. designed experiments. S.M., S.A.T., J.A.S., M.H., J.C., M.I., and K.W. conducted behavioral experiments. J.A.S. and J.W. generated tissues for RNA sequencing. F.J.S. helped with RNA sequencing analysis. M.K.L. and R.C. generated and provided custom viral constructs. S.M. and S.A.T. performed statistical analyses. S.M. wrote the manuscript with review from D.M.D.
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Mitra, S., Thomas, S.A., Martin, J.A. et al. EGR3 regulates opioid-related nociception and motivation in male rats. Psychopharmacology 239, 3539–3550 (2022). https://doi.org/10.1007/s00213-022-06226-1
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DOI: https://doi.org/10.1007/s00213-022-06226-1