Activation of NK1 receptors in the locus coeruleus induces analgesia through noradrenergic-mediated descending inhibition in a rat model of neuropathic pain

BACKGROUND AND PURPOSE The locus coeruleus (LC) is a major source of noradrenergic projections to the dorsal spinal cord, and thereby plays an important role in the modulation of nociceptive information. The LC receives inputs from substance P (SP)-containing fibres from other regions, and expresses the NK1 tachykinin receptor, a functional receptor for SP. In the present study, we investigated the roles of SP in the LC in neuropathic pain. EXPERIMENTAL APPROACH Chronic constriction injury (CCI) of the left sciatic nerve was performed in rats to induce neuropathic pain. After development of neuropathic pain, SP was injected into the LC and the nocifensive behaviours were assessed. The involvement of noradrenergic descending inhibition in SP-induced analgesia was examined by i.t. administration of yohimbine, an a2-adrenoceptor antagonist. NK1 receptor expression in the LC was examined by immunohistochemistry. KEY RESULTS In CCI rats, mechanical allodynia was alleviated by SP injection into the LC. These effects were abolished by prior injection of WIN 51708, an NK1 receptor antagonist, into the LC or i.t. treatment with yohimbine. NK1 receptor-like immunoreactivity was observed in noradrenergic neurons throughout the LC in intact rats, and remained unchanged after CCI. CONCLUSION AND IMPLICATIONS SP in the LC exerted analgesic effects on neuropathic pain through NK1 receptor activation and resulted in facilitation of spinal noradrenergic transmission. Accordingly, manipulation of the SP/NK1 receptor signalling pathway in the LC may be a promising strategy for effective treatment of neuropathic pain.