Blockade of the orexin receptors in the ventral tegmental area could attenuate the stress-induced analgesia: A behavioral and molecular study

Exposure to stressful stimuli induces various physiological and behavioral responses, affects pain perception, and alters gene expression. Stress elicits an analgesic effect in laboratory animals, termed the “stress-induced analgesia” (SIA). Orexin neuropeptides, processed from pre-pro-orexin in the hypothalamus, release during stress and are known to be antinociceptive. The current study examined the modulatory role of the ventral tegmental area (VTA) orexinergic system in the restraint SIA and extracellular signal-regulated kinase (ERK) activation in the nucleus accumbens (NAc). Adult male Wistar rats were subjected to intra-VTA injection of orexin-1 and -2 receptor antagonists (SB334867 and TCS OX2 29; 1, 3, 10, and 30 nmol/0.3 μl, respectively) five min before a 3-h period of exposure to restraint stress (RS). Western blot analysis was also used to assess the levels of ERK and phosphorylated ERK (p-ERK) in the NAc tissues. RS exposure produced an analgesic response to the thermal pain model (Tail-flick test). RS-induced antinociception was inhibited by intra-VTA administration of SB334867 and TCS OX2 29. Moreover, in the molecular study, exposure to forced swim stress (FSS) and RS significantly enhanced the p-ERK/ERK ratio. Blockade of both orexin receptors diminished the p-ERK/ERK ratio, but this decrease was significant only in the FSS group of animals that received TCS OX2 29. Collectively, the present findings suggested the functional roles of intra-VTA orexin receptors and ERK signaling in the SIA.