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

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.