Papers of the Week

Chronic opioid exposure induces tolerance to the pain-relieving effects of opioids but sensitization to some other effects. While the occurrence of these adaptations is well-understood, the underlying cellular mechanisms are less clear. This study aimed to determine how chronic treatment with morphine, a prototypical opioid agonist, induced adaptations to subsequent morphine signaling in different subcellular contexts. Opioids acutely inhibit glutamatergic transmission from medial thalamic (MThal) inputs to the dorsomedial striatum (DMS) via activity at μ-opioid receptors (MORs). MORs are present in somatic and presynaptic compartments of MThal neurons terminating in the DMS. We investigated the effects of chronic morphine treatment on subsequent morphine signaling at MThal-DMS synapses and MThal cell bodies in male and female mice. Surprisingly, chronic morphine treatment increased subsequent morphine inhibition of MThal-DMS synaptic transmission (morphine facilitation) in male, but not female, mice. At MThal cell bodies, chronic morphine treatment decreased subsequent morphine activation of potassium conductance (morphine tolerance) in both male and female mice. In knockin mice expressing phosphorylation-deficient MORs, chronic morphine treatment resulted in tolerance to, rather than facilitation of, subsequent morphine signaling at MThal-DMS terminals, suggesting phosphorylation-deficiency unmasks adaptations that counter the facilitation observed at presynaptic terminals in wild-type mice. The results of this study suggest that the effects of chronic morphine exposure are not ubiquitous; rather adaptations in MOR function may be determined by multiple factors such as subcellular receptor distribution, influence of local circuitry and sex. Repeated opioid use causes tolerance to their pain-relieving effects but can exacerbate some undesirable effects limiting their clinical utility. A detailed understanding of the physiological adaptations that contribute to the development of tolerance is critical to develop mitigation strategies. This study found that within medial thalamic projection neurons, chronic morphine treatment induced adaptations that were not ubiquitous. Instead, prior morphine exposure increased morphine effects at thalamic terminals in the dorsomedial striatum only in male mice, but decreased morphine effects at medial thalamic cell bodies in both sexes. In mice lacking phosphorylation sites on MOR, chronic morphine treatment decreased, rather than increased, morphine effects at thalamic terminals in the dorsomedial striatum, implicating receptor phosphorylation in driving adaptations observed in wild-type mice.