Opioid dependence is accompanied by neuroplastic changes in reward circuitry leading to a negative affective state contributing to addictive behaviors and risk of relapse. The current study presents a neuroimmune mechanism through which chronic opioids disrupt the ventral tegmental area (VTA) dopaminergic circuitry that contributes to impaired reward behavior. Opioid dependence was induced in rodents by treatment with escalating doses of morphine. Microglial activation was observed in the VTA following spontaneous withdrawal from chronic morphine treatment. Opioid-induced microglial activation resulted in an increase in brain-derived neurotrophic factor (BDNF) expression and a reduction in the expression and function of the K+Cl− co-transporter KCC2 within VTA GABAergic neurons. Inhibition of microglial activation or interfering with BDNF signaling prevented the loss of Cl− extrusion capacity and restored the rewarding effects of cocaine in opioid-dependent animals. Consistent with a microglial-derived BDNF-induced disruption of reward, intra-VTA injection of BDNF or a KCC2 inhibitor resulted in a loss of cocaine-induced place preference in opioid-naïve animals. The loss of the extracellular Cl− gradient undermines GABAA-mediated inhibition, and represents a mechanism by which chronic opioid treatments can result in blunted reward circuitry. This study directly implicates microglial-derived BDNF as a negative regulator of reward in opioid-dependent states, identifying new therapeutic targets for opiate addictive behaviors.

Microglial activation in the spinal cord plays a central role in the development and maintenance of chronic pain following a peripheral nerve injury. To date, there has not been a thorough assessment of microglial activation in brain regions associated with pain and reward. To this end, we used a mouse model of neuropathic pain, whereby the left sciatic nerve of male C57Bl/6J mice was loosely constricted (chronic constriction injury) and assessed microglial activation in several brain regions two weeks following injury, a time point where pain hypersensitivity is well established. We found significant microglial activation in brain regions associated with sensory pain transmission and affect, including the thalamus, prefrontal cortex, and amygdala. Activation was consistently most robust in brain regions contralateral to the side of injury. Brain regions not directly involved in either the sensory of affective dimensions of pain, such as the motor cortex, did not display microglial activation. This study confirms that peripheral nerve injury induces microglial activation in regions involved with both sensory and affective components of pain.

Activation of the kappa opioid receptor (KOR) produces analgesia without euphoria and is emerging as a target for chronic pain and itch without abuse potential. The KOR system is also notable for a significant sex difference, with females less responsive to KOR agonists than males

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