Locus Coeruleus mediates the pharmacological effects of 2-Pentadecyl-2-oxazoline in a mouse model of neuropathic pain.

Current neuropathic pain treatments are often ineffective and carry significant side effects, highlighting the need for new therapeutic approaches. Therefore, alternative strategies, such as the use of natural compounds with potential analgesic properties, are actively being pursued. These agents offer the potential for safer and more effective pain management. One such compound, 2-pentadecyl-2-oxazoline (C15OXA), has shown efficacy in alleviating chronic pain and its associated neuropsychiatric symptoms. Despite its promising effects, the precise mechanisms underlying C15OXA's action remain poorly understood. Previous studies suggest that it functions as both an α2-adrenergic receptor antagonist and a histamine H3 receptor modulator. In this study, we aimed to further elucidate the mechanisms of C15OXA, with a particular focus on the role of locus coeruleus (LC) neuron activity. To investigate this, we employed a chemogenetic approach to chronically silence LC noradrenergic neurons in a male mouse model of neuropathic pain induced by spared nerve injury (SNI). Our results revealed that: (i) LC inhibition abolished the anti-hypersensitivity effects of C15OXA; (ii) LC DREADD-inhibition attenuated C15OXA-induced sedative-like effects; (iii) LC inhibition enhanced the antidepressant-like effects of C15OXA; (iv) nest-building behavior, disrupted by C15OXA, was restored by LC silencing; and (v) silencing the LC attenuated the C15OXA-induced increase in LC activity and in noradrenergic fibers density in the spinal cord, as evidenced by reduced levels of phosphorylated CREB (pCREB) and dopamine-β-hydroxylase (DBH), respectively. These findings suggest a therapeutic relevance of C15OXA in neuropathic pain and support a possible involvement of the LC in mediating its behavioral and molecular effects.