Sensitivity of Affective Pain Circuits to Inhibitory G Protein‐Coupled Receptor Signaling

Abstract

Opioids modulate both sensory and affective components of pain, most significantly through agonist activity at the mu‐opioid receptor (MOR). While cellular mechanisms underlying opioid modulation of perception of stimulus intensity have been well characterized, mechanisms underlying opioid effects on pain‐related negative affect have not been well elucidated. The mediodorsal thalamus (MD) sends glutamatergic projections to the striatum as part of a thalamo‐cortical‐striatal loop that is involved in affective pain perception. Here, we determined the ability of various inhibitory coupled G‐protein coupled receptors (GPCRs), including MOR to inhibit glutamate release via presynaptic mechanisms. In mouse brain slices, MD terminals in the striatum were selectively activated using optogenetic techniques. Excitatory postsynaptic (EPSCs) were measured in striatal medium spiny neurons using whole cell patch‐clamp electrophysiology in the presence and absence of various inhibitory GPCR agonists. MOR full agonists met‐enkephalin (ME) and fentanyl, the delta opioid receptor agonist DPDPE, the adenosine A1 receptor agonist CPA, the GABAB receptor agonist baclofen, and the CB1 receptor agonist WIN 55,212 were tested. EPSC inhibition was seen with application of ME, fentanyl, CPA, and baclofen, indicating the presence of MORs, A1, and GABAB receptors. Inhibition was not seen with application of DPDPE or WIN 55,212, indicating delta opioid receptors and CB1 receptors are not present on these terminals. The effect of chronic opioid treatment on the function of these GPCRs will be discussed. Overall these data provide insight into how presynaptic GPCRs function to regulate neurotransmission in a circuit important for affective pain perception. Support or Funding Information NIH T32‐DA007281R01DA042779