ELContribution of orexinergic receptors within the ventral tegmental area in restraint stress-induced analgesia in the persistent inflammatory pain model

Behav Brain Res. 2026 Mar 15:116164. doi: 10.1016/j.bbr.2026.116164. Online ahead of print.

ABSTRACT

Stress-induced analgesia is a phenomenon during which exposure to stressors suppresses pain perception. Previous studies have shown that stress triggers the lateral hypothalamus's orexin neurons to project to the ventral tegmental area (VTA), where orexinergic receptors are involved in nociceptive responses. The present study examined the hypothesis that orexinergic receptors located in the VTA region could potentially influence the progression of stress-induced analgesia in a persistent inflammatory pain model. One hundred and thirteen adult male Wistar rats (230 - 250g) received different doses (1, 3, 10, and 30 nmol/0.3μL) of orexin 1 receptor (OX1r) antagonists (SB334867) and orexin 2 receptor (OX2r) antagonists (TCS OX2 29) unilaterally in the VTA. Five minutes later, the animal was exposed to restraint stress (RS) for 3hours, and then their nociceptive threshold was evaluated using the formalin test. According to the study's findings, injecting OX1r and OX2r antagonists into the VTA did not affect the nociceptive threshold in the formalin test. Still, it did lessen the analgesia RS caused during both test phases. In the early and late phases, OX2r and OX1r antagonists were both equally effective. This is true even though neither the drugs nor the vehicles impacted the animals' locomotor activity. The findings suggest that the mechanisms responsible for RS-induced pain relief entail the involvement of OX1r and OX2r in the VTA.

PMID:41846006 | DOI:10.1016/j.bbr.2026.116164