The ENK^{RVM →SRD} Projection Constitutes a Functionally Specific Circuit for Bidirectional Pain Modulation

Chronic pain management remains a major clinical challenge due to the limited availability of effective therapies that avoid severe side effects. The rostral ventromedial medulla (RVM) is a critical brainstem center for pain modulation; however, the neurochemical identity and functional roles of its neuronal subpopulations remain incompletely understood.

We performed a series of tests by constructing a complete Freund's adjuvant (CFA)-induced inflammatory nociceptive model and a chronic constrictive injury (CCI) neuropathic pain model combined with behavioral experiments, in situ hybridization, chemogenetics, optogenetics, and in vivo electrophysiological techniques.

This study identifies enkephalinergic neurons in the RVM and their projections to the subnucleus reticularis dorsalis (SRD) as a distinct descending pain-inhibitory circuit. RNAscope shows elevated ENK^RVM neuron activity in mouse models of inflammatory and neuropathic pain. Bidirectional chemogenetic and optogenetic manipulations demonstrate that inhibiting ENK^RVM neurons or their SRD projections induces hyperalgesia, while activation elevates baseline pain thresholds and reverses hyperalgesia in CFA and CCI models. This pathway modulates nociception selectively without affecting anxiety or motor function.

These findings identify the ENK^RVM→SRD pathway as a bidirectional descending circuit for pain inhibition, highlighting its potential as a therapeutic target for analgesic intervention.