PARAVENTRICULAR THALAMUS INPUTS TO THE NUCLEUS ACCUMBENS MODULATE DOPAMINE SIGNALING AND OPIOID RESPONSES IN CHRONIC PAIN

The nucleus accumbens (NAc) is a central hub for motivational and behavioral regulation and plays an important role in pain processing and psychiatric disorders such as depression. The NAc receives diverse afferent inputs, including projections from the paraventricular thalamus (PVT), which have been implicated in inflammatory pain. Here, we aimed to determine how PVT–NAc projections influence dopamine and glutamate signaling, how this circuitry is altered in chronic pain, and how opioidergic drugs such as morphine modulate these processes.

We combined fiber photometry with chemogenetic manipulation using DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) in a mouse model of chronic inflammatory pain. Dopamine activity in the NAc was monitored using the genetically encoded sensor dLight1.3b following morphine administration in mice with Complete Freund’s Adjuvant (CFA)–induced pain. To assess the contribution of PVT inputs, we performed photometry in anesthetized animals during electrical stimulation of PVT projections. We then extended these findings to awake animals by selectively expressing Cre-dependent DREADDs in the PVT alongside dopamine sensors in the NAc, in both control and CFA-treated mice.

Our results demonstrate that chronic pain alters morphine-induced dopamine activity in the NAc. These changes can be partially attributed to modulation of PVT inputs to the NAc.

Overall, our findings identify the PVT–NAc pathway as a key regulator of dopamine dynamics and pain processing, highlighting this circuit as a potential target for improving opioid efficacy in chronic pain states.