Role of Orexin-A receptors within the Locus Coeruleus in the antinociception induced by microinjection of carbachol into the lateral hypothalamus

Introduction: Previous studies have shown that stimulation of lateral hypothalamus (LH) produces antinociception. Orexin-A (OXA) receptor is strongly expressed in the nucleus locus coeruleus (LC) and orexinergic fibers densely project from LH to LC. In this study, we assessed the role of LC and its OXA receptors in antinociceptive response induced by LH chemical stimulation in the rat. Methods: The cholinergic agonist carbachol (125nmol/0.5μl saline) and lidocaine (2% 0.5μl) were unilaterally microinjected into the LH with the concurrent LC inactivation. In another set of experiments, SB-334867 an OXA selective antagonist or its vehicle were unilaterally infused in LC to study its effect on LH stimulation-induced antinociception. Antinociceptive responses were obtained by the tail flick test and were presented as maximal possible effect (MPE) at 5, 10, 15, 20, 30 and 60 min after drug administrations. Results: The results showed that microinjection of carbachol into the LH significantly induced antinociception at 5 and 10 min (p<0.001). This effect was significantly blocked by microinjection of lidocaine into the LC. Additionally, intra-LC administration of SB-334867 (4.5 μg) could suppress the LH stimulation-induced antinociception by carbachol at 5 and 10 min post-injection times (p<0.001). Conclusion: Our findings showed that analgesic response induced by LH stimulation is mediated in part by the subsequent activation of LC neurons and results from the activation of orexinergic inputs into the LC that can modulate the pain processing.