Orexinergic–Opioidergic Interactions Within the Nucleus Accumbens in the Modulation of Acute Pain: Evidence From the Tail-Flick Test in Rats Publisher



Jolani M S ; Mohammadi M ; Mozafari R ; Haghparast A
Source: Journal of Integrative Neuroscience Published:2026

Abstract

Background: The nucleus accumbens (NAc) plays a central role in integrating motivational, reward-related, and nociceptive inputs. Opioid and orexin systems within the NAc are both implicated in pain modulation, yet their functional interaction in acute nociception is not fully understood. This study examined the interplay between opioidergic and orexinergic signaling in the NAc during acute pain processing. Methods: Adult male Wistar rats underwent unilateral intra-NAc administration of morphine (5, 10, 25, and 50 mmol) to assess dose-dependent antinociception using the tail-flick test. Orexinergic involvement was evaluated by intra-NAc injection of orexin-A (0.25, 0.5, 1, and 2 nmol), the orexin receptor type 1 (OX1R) antagonist SB334867 (3, 10, 30, and 100 nmol), or the orexin receptor type 2 (OX2R) antagonist TCS OX2 29 (3, 10, 30, and 100 nmol). To assess functional interactions, naloxone was administered prior to orexin-A, and SB334867 or TCS OX2 29 were given before morphine. Results: Intra-NAc injections of morphine and orexin-A produced significant and dose-dependent antinociceptive effects. Pre-treatment with SB334867 or TCS OX2 29 markedly reduced the analgesic responses induced by both morphine and orexin-A. Likewise, naloxone pre-treatment significantly attenuated orexin-A-evoked antinociception. Conclusions: These findings indicate a bidirectional interaction between opioidergic and orexinergic systems within the NAc in regulating acute nociception. The demonstrated functional crosstalk suggests that targeting orexinergic pathways may enhance endogenous analgesic mechanisms and could potentially reduce opioid requirements in clinical pain management. © 2026 The Author(s).