Opposing effects of mu opioid receptors on dopamine D1 and D2 receptor expressing neurons in opioid mediated antinociception

Abstract

There is extensive interaction between systems involved in pain processing and motivation, where the aberrant functioning of salience circuits likely contributes to chronic pain, as well as increased susceptibility to opioid misuse and opioid use disorder. This study asks to what extent mu opioid receptors (MORs) in dopamine D1 receptor (D1R), D2 receptor (D2R) or adenosine A2a receptor (A2aR) expressing neurons contribute to the expression of pain and opioid antinociception. We ablated MORs in dopamine receptor expressing neurons by breeding D1R, D2R or A2aR-cre with MOR^loxP mice, which was confirmed by RNAscope multiplex fluorescent in situ hybridization. To determine the role of these MORs in nociception, we assessed the nociceptive responses in the hot plate and formalin tests with and without treatment with oxycodone (3 mg/kg, i.p.). Pain-like behavior in a thermal assay, mechanical thresholds following nerve injury, and the formalin test were not altered by genotype. However, oxycodone-induced antinociception in the formalin test was differentially altered. Opioid antinociception was attenuated in mice that lacked MORs in D1R neurons, but was enhanced when MORs were ablated in either the D2R and A2aR neurons. In contrast, there was no effect of genotype on oxycodone-induced antinociception in the thermal nociceptive test. Together, these data show that MORs in D1R expressing neurons is necessary for opioid-induced antinociception in a model of tonic inflammatory pain, but not acute thermal pain. Whereas, MOR in D2R and A2aR expressing neurons had a tonic inhibitory tone on opioid-mediated antinociception in the formalin test. PERSPECTIVE: This article presents evidence that mu opioid receptors in dopamine receptor containing neurons differentially modulate opioid antinociception in the formalin test but not threshold evoked phasic pain. The endogenous opioid system in these neuronal populations does not appear to modulate various pain behaviors.

Keywords: Analgesia; Antinociception; Dopamine; Dopamine receptor; Formalin test; Medium spiny neuron; Morphine; Neuropathic pain; Opiate; Opioid; Pain; Striatum; Thermal pain.