NLRP3-mediated neuroinflammation in the ventrolateral orbital cortex contributes to the formation of morphine-induced addiction memory by upregulating GRIN3B.

Addiction is a prevalent adverse effect of opioid analgesics. Morphine, a frequently employed opioid analgesic in clinical practice, has been demonstrated to possess rewarding properties that contribute to the establishment of addiction memory. Morphine administration elicits the NOD-like receptor protein 3 (NLRP3)-mediated neuroinflammatory response. Neuroinflammation can modulate the expression of GRIN/NMDAR (glutamate ionotropic receptor NMDA type), a key determinant of synaptic plasticity and memory formation. For this reason, we performed morphine conditioned place preference test to observe the effects of behavioral training, inhibition of NLRP3, and Grin3b knockout on the formation of addiction memory. Repeated morphine administration caused NLRP3-relative neuroinflammation, increased GRIN3B protein expression, and contributed to the formation of addiction memory in a task-dependent manner. Inhibiting NLRP3 attenuated neuroinflammation, decreased astrocyte activation and GRIN3B levels, and inhibited the formation of morphine-induced addiction memory by altering synaptic structure. Knocking out Grin3b impeded the formation of addiction memory but did not alleviate neuroinflammation or glial cells activation. Our findings indicate that NLRP3-mediated neuroinflammation modulates synaptic plasticity and contributes to the formation of morphine-induced addiction memory through GRIN3B.