AUTHOR=Kibret Berhanu , Onaivi Emmanuel S. , Sharma Venkatanarayanan 
  
TITLE=Distinct contributions of mu opioid and CB2 cannabinoid receptors to neuroimmune and behavioral responses
  
JOURNAL=Advances in Drug and Alcohol Research
  
VOLUME=Volume 6 - 2026
  
YEAR=2026
  
URL=https://www.frontierspartnerships.org/journals/advances-in-drug-and-alcohol-research/articles/10.3389/adar.2026.16646
  
DOI=10.3389/adar.2026.16646
  
ISSN=2674-0001
  
ABSTRACT=Marijuana (cannabis) and cannabinoids are getting global medical and recreational approvals in this era of the opioid epidemic. Both opiates and cannabis are often co-abused, and their use increases the risk of opioid and cannabis use disorders (OUDs and CUDs), and dependency. Opioid and cannabinoid systems share many neuromodulating and pharmacological effects by activating opioid and cannabinoid receptors, respectively. Inflammation is increasingly implicated in many diseases, and mu-opioid receptor (MOR) and CB2 cannabinoid receptor (CB2R) have been linked to neuroinflammation. The hypothesis that changes in MOR and CB2R mediated behavioral and cytokine alterations are associated with their roles in inflammation was tested here. Naïve male C57Bl/6J as wild type, MOR KO mice with deletion of MOR, DAT-Cnr2 cKO mice with deletion of CB2R from dopamine neurons and CX3Cr1-Cnr2 cKO mice with deletion of CB2R from microglia were used in the study. Nociception was assessed using tail-flick latency, followed by ELISA to quantify levels of cytokines and chemokines in the cerebellum and prefrontal cortex (PFC) regions of the animals. MOR KO, DAT-Cnr2, and CX3Cr1-Cnr2 conditional knockout mice exhibited distinct behavioral and neuroimmune phenotypes, marked by genotype- and region-specific alterations in cytokines and chemokine. CX3Cr1-Cnr2 cKO mice had reduced tail-flick sensitivity compared to MOR KO, DAT-Cnr2 cKO, and wild-type controls. These findings suggest that MOR deletion and cell-specific loss of CB2Rs in dopamine neurons or microglia distinctly affect nociceptive functions, alongside immune signaling changes. Targeting components of the eCBome and opioid systems may offer novel therapeutic strategies for inflammation-linked chronic pain.