Characterizing the Sensory and Affective Phenotype of Kappa Opioid Receptor Cre Knockin Mice in Response to Chronic Variable Stress and Inflammation

Abstract

Kappa Opioid Receptors (KORs) are an alternative opioid targeting site with the potential of targeting pain without the abuse associated with Mu Opioid Receptors (MORs). KORs have been linked to nociception and mood, and modulate responses to chemical, mechanical and thermal nociceptive stimuli. The KOR‐Cre knockin model is a novel method used to drive expression of the exogenous protein Cre recombinase using the endogenous KOR locus. While this model allows for study and visualization of KOR‐expressing cells, the full consequences of losing either one or both KOR alleles in these mice is not well characterized. We evaluated the sensory and affective phenotype of KOR‐Cre knockin homozygous and heterozygous mice before and after a 10‐day chronic variable stress (CVS) paradigm and the induction of inflammatory pain with Complete Freund's Adjuvant (CFA). We tested for mechanical (von Frey) and thermal (Hargreaves) sensory behavior, as well as depressive and anxiolytic affective behavior. We report sex‐specific differences in the sensory, but not affective phenotype in this model. We observe decreased depressive and increased anxiolytic behavior in KOR‐Cre heterozygous mice post‐CVS. Male mice exhibit mechanical hypersensitivity while both sexes of KOR‐Cre homozygous mice exhibit thermal hyposensitivity post‐CVS. Administration of CFA elicits contralateral thermal hyposensitivity in male KOR‐Cre heterozygous and female homozygous mice, while no changes in mechanical sensitivity are observed in either sex. We conclude that sex‐specific differences must be accounted for when conducting pain research, as CVS and CFA results in variation in pain incidence between sexes. Moreover, lack of activity in KOR‐Cre homozygous mice post‐CVS may result in signs of pain resilience in the absence of the receptor under stress. Furthermore, hyposensitivity post‐CFA could indicate that pain‐related function in KORs may act through a synergistic compensatory mechanism combining the activity of both MORs and KORs. Our results suggest that caution should be used when substituting KOR‐Cre heterozygous mice for WT mice. By characterizing this model, we provide a baseline for which the model can be compared to when conducting research on KOR‐positive cells.Support or Funding InformationResearch supported by NIH R25NS100118 (BJK, KJT, MC, MRM) and the APS UGRSF (MZ).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.