Hyperbaric oxygen (HBO₂) induces a two‐phase antinociceptive response of unusually long duration in mice

Abstract

HBO2 is approved by the FDA for limited clinical indications but not for chronic pain. Earlier we showed that HBO2 treatment produces an antinociceptive effect mediated by nitric oxide (NO) and opioid mechanisms [Zylstra et al., FASEB J 22, 711.16 & 711.17, 2008]. In this study, we assessed the antinociceptive effect of multiple HBO2 treatments. Male NIH Swiss mice (20‐30 g) were exposed to HBO2 at 2.5 ATA for 4×60‐min then returned to their home cages for different time intervals before testing with the acetic acid‐induced abdominal constriction test. Results revealed a robust antinociception of at least 6 hr after the last HBO2 treatment. This response was followed a day later by an emerging and equally robust late‐phase antinociceptive effect that surprisingly lasted for two weeks following the last HBO2 treatment. The early phase was antagonized by pretreatment with naltrexone (NTX) and the late phase was antagonized by the selective 5‐HT1A antagonist WAY‐100635 but not NTX. Continuous treatment with NTX or the NO synthase‐inhibitor L‐NAME during the 4 days of HBO2 treatment also reduced the late‐phase response. Based on these findings, we suggest that the early‐phase antinociception involves an opioid pathway, while the longer‐acting late‐phase antinociception involves an NO‐opioid‐5‐HT1A pathway. (Supported in part by NIH Grant GM‐77153, the College of Pharmacy and the Chico Hyperbaric Center.)