Lateral hypothalamic orexinergic neurons as central mediators of pain modulation and non-pharmacological analgesia

Pain is a complex sensory and affective experience regulated by distributed neural circuits that integrate internal physiological states with external stimuli. Orexinergic neurons, a widely projecting neuronal population within the lateral hypothalamus (LH), play a central role in this process. This review synthesizes current evidence on the involvement of LH orexinergic neurons in nociceptive regulation and highlights their role as a key integrative substrate for non-pharmacological analgesia. Orexin peptides (orexin A and orexin B) modulate both the sensory-discriminative and affective-motivational components of pain via their receptors (OX1R and OX2R) in a context-dependent manner, producing antinociceptive or pro-nociceptive effects depending on peptide subtype, receptor distribution, circuit architecture, and pain modality. In parallel, emerging evidence indicates that orexinergic neurons are critically engaged in diverse non-pharmacological analgesic paradigms, including stress-induced analgesia, olfactory modulation, electroacupuncture, and exercise-induced hypoalgesia. In addition, other neuronal populations within the LH, such as glutamatergic, GABAergic, and neurotensinergic neurons, also contribute to pain regulation in a circuit-specific manner and partially overlap anatomically and functionally with orexinergic neurons. Collectively, these findings position LH orexinergic neurons as a central node linking neural circuit dynamics with the behavioral and physiological modulation of pain. Targeting orexin-related pathways may therefore provide novel avenues for the development of non-pharmacological and integrative pain management strategies.