Orexin-A reduces inflammatory pain via mu-opioid receptor interaction in rat dentate gyrus

The hippocampal formation, particularly the dentate gyrus (DG), plays a crucial role in processing the multidimensional experience of pain, encompassing sensory, emotional, and cognitive components. Current pain management strategies often fall short, highlighting the need for novel targets. Both the opioid and orexin systems independently modulate pain, with opioids affecting nociception and emotional aspects, and orexins linking pain to arousal and autonomic responses. This study specifically investigates the previously underexplored interaction between these two systems within the DG in modulating inflammatory pain.

Researchers utilized 118 adult male Wistar rats to investigate the interaction of orexinergic and opioidergic receptors in the DG. Animals received intra-DG microinjections of Orexin-A (0.5-2 nmol), the OX1R antagonist SB334867 (3-100 nmol), or the mu opioid receptor antagonist Naloxone (5-45 nmol), either alone or in combination with Morphine (25 nmol). All microinjections (volume 0.5 μl) were administered 5 min before intra-DG orexin-A or morphine. Formalin (2.5%, 50 μl) was then injected subcutaneously into the hind paw 5 min later to induce biphasic inflammatory pain, with nociceptive behaviors recorded during early (first 5 min) and late (last 45 min) phases as the primary endpoint. Locomotor activity tests were also performed.

Intra-DG administration of Orexin-A (0.5-2 nmol) significantly reduced nociceptive behaviors across both the early and late phases of formalin-induced pain, demonstrating potent analgesic effects. This suggests a direct role for orexin-A in modulating inflammatory pain within the dentate gyrus. The study further revealed a critical interaction between the orexinergic and opioidergic systems: > Pre-treatment with either the OX1R antagonist SB334867 (3-100 nmol) or the mu opioid receptor antagonist Naloxone (5-45 nmol) significantly attenuated the antinociceptive effects induced by orexin-A. This indicates that orexin-A's pain-reducing actions are at least partially mediated through both OX1R and mu opioid receptor mechanisms. Moreover, co-administration of SB334867 with Morphine (25 nmol) significantly inhibited morphine-induced antinociceptive responses, further supporting a functional interaction between these two systems in the DG. Locomotor activity tests confirmed that the observed effects were specific to pain modulation and not due to impaired general motor function.