UCLA

Mu opioid receptor (MOR) activation has important effects on reward circuits through its modulation of dopamine release in the ventral striatum. Studies suggest that dopamine is also important in chronic pain states where D2/D3 agonists can alleviate pain (Faramarzi et al. 2016). It is also known that MORs in the striatum are highly expressed (Mansour et al. 1995) but it remains unclear to what extent their expression in the striatum contributes to opioid-mediated analgesia. My dissertation research aimed to determine the role of MORs expressed on D1 receptor containing medium spiny neurons located in the nucleus accumbens shell in opioid reward and opioid reinforcement in chronic pain states. Unpublished research in the Cahill Lab indicated that deletions of MORs from D1 neurons ablated opioid-induced analgesia in the formalin test and in a model of neuropathic pain. In my study, I postulate that MORs on D1- receptor containing neurons in the nucleus accumbens shell are necessary and sufficient to produce opioid induced analgesia in a chronic pain model. I used a chronic constriction injury model of neuropathic pain that produced mechanical allodynia within a week of nerve injury. I used genetically modified mice where D1 receptor-cre mice were bred with MORloxP mice to ablate MOR from the D1 receptor expressing neurons. Re-expression of MOR into the nucleus accumbens shell was achieved by bilateral injection of AAVDJ-hSyn1-DIO-mCherry-2A-MOR. The control virus, AAVDJ-hSyn-DIO-mCherry, was used to assess the effects of MOR reinsertion by the active virus. Behavioral outcomes were assessed via acute thermal threshold testing using the hot plate test and opioid preference using conditioned place preference tests. I established that the ablation of MORs from these neurons had no effect on opioid-mediated analgesia in an acute thermal test. I also re-produced previous data that the absence of MORs from D1 receptor expressing neurons prevented opioid-mediated conditioned place preference in both naive and neuropathic pain animals. This study also found no significant differences in the behaviors of animals between the active and control virus conditions. Immunohistochemical experiments were conducted to confirm viral expression and target. Control virus showed expression in the nucleus accumbens shell as expected, however, the active virus showed no expression suggesting that the virus was not active. This study identified that opioid-mediated analgesia in acute threshold tests does not require the expression of MOR in D1 receptor containing neurons. It also identified that MOR in D1 receptor expressing neurons was necessary for opioid-mediated reward and negative reinforcement. However, due to problems with the virus, we were not able to identify site specificity of this effect.