The analgesic effect of neuropeptide S (NPS) in alcohol-dependent male and female rats

Introduction: Alcohol dependence (AD) includes tolerance to alcohol's analgesic effects and increased pain sensitivity during withdrawal (i.e., hyperalgesia). Further, the reciprocal relationship between alcohol use and pain sensitivity is hypothesized to contribute to the maintenance of AD through negative reinforcement (i.e., self-medication). The neuropeptide S (NPS) system, known to regulate stress, arousal, and pain pathways, may offer a therapeutic target to ameliorate AD-induced hyperalgesia. Given previous reports on the antinociceptive properties of NPS, we hypothesized that central administration of NPS could attenuate the heightened pain sensitivity observed in AD rats.

Methods: Male (n = 11) and female (n = 7) Wistar rats were surgically implanted with an intracerebroventricular (ICV) cannula and assigned to either the AD or alcohol-naïve control group, matched in terms of their baseline thermal nociceptive thresholds. Pain sensitivity was tracked weekly using thermal (Hargreaves) and mechanical (robotic Von Frey, also known as the dynamic plantar aesthesiometer) assays to establish AD-induced hyperalgesia. After stable hyperalgesia emerged, rats received ICV NPS administrations (0, 0.1, or 1 nmol in 5 μL saline) 5 min prior to pain testing (Experiment 1: Hargreaves; Experiment 2: robotic Von Frey). In a follow-up experiment, three Von Frey methods (electronic, robotic, and manual) were compared to assess their efficacy in detecting AD-induced mechanical hyperalgesia.

Results: AD male and female rats developed significant hyperalgesia across both pain modalities. Central administration of NPS produced robust analgesia in a dose-dependent manner in both AD and alcohol-naïve control rats. No sex differences were observed in baseline nociception, AD-induced hyperalgesia, or NPS-induced analgesia. All three mechanical assays reliably detected AD-induced mechanical hyperalgesia, and the importance of adequate habituation procedures is discussed.

Conclusion: These findings indicate that NPS exerts a robust analgesic effect in male and female rats. This effect appears independent of ethanol-exposure history but produces sufficient analgesia to alleviate pain sensitivity in hyperalgesic AD rats to/beyond the level of sensitivity in vehicle treated, alcohol-naïve controls. The NPS system may therefore represent a promising, non-addictive target for treating pain-related symptoms in alcohol dependence.

Alcohol; Alcohol use disorder; And sex differences; Hyperalgesia; Neuropeptide S; Pain.