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Central control of opioid-induced mechanical hypersensitivity and tolerance in mice

Guangjuan Yin,Kaifang Duan,Dong Dong,Feng Du,Chao Guo,Changyi Zhang,Xi Liu,Yuanjie Sun,Tianwen Huang,Guangfu Cui,Longzhen Cheng

Repetitive use of morphine (MF) and other opioids can trigger two major pain-related side effects: opioid-induced hypersensitivity (OIH) and analgesic tolerance, which can be subclassified as mechanical and thermal. The central mechanisms underlying mechanical OIH/tolerance remain unresolved. Here, we report that a brain-to-spinal opioid pathway, starting from μ-opioid receptor (MOR)-expressing neuron in the lateral parabrachial nucleus (lPBN MOR+ ) via dynorphin (Dyn) neuron in the paraventricular hypothalamic nucleus (PVH Dyn+ ) to κ-opioid receptor (KOR)-expressing GABAergic neuron in the spinal dorsal horn (SDH KOR-GABA ), controls repeated systemic administration of MF-induced mechanical OIH and tolerance in mice. The above effect is likely mediated by disruption of dorsal horn gate control for MF-resistant mechanical pain via silencing of the Dyn-positive GABAergic neurons in the SDH (lPBN MOR+ → PVH Dyn+ → SDH KOR-GABA → SDH Dyn-GABA ). Repetitive binding of MF to MORs during repeated MF administration disrupted the above circuits. Targeting the above brain-to-spinal opioid pathways rescued repetitive MF-induced mechanical OIH and tolerance.