br Acknowledgements Research was funded by
Acknowledgements Research was funded by the Natural Sciences and Engineering Council of Canada (NSERC) (Grant #210290) SGF. The funding body played no role in the design or execution of the study. The authors declare no conflict of interest.
Introduction HBO2 therapy is the use of 100% oxygen (O2) at higher-than-atmospheric pressures for limited periods of time (generally 60–90 min) to achieve beneficial clinical outcomes. HBO2 therapy is approved by the U.S. Food and Drug Administration (FDA) for only limited clinical indications, which include decompression sickness, carbon monoxide poisoning, wound healing and delayed 4SC-202 injury (Weaver, 2014). The use of HBO2 to treat chronic pain is the subject of ongoing research in both clinical and preclinical research. Clinically, HBO2 treatment is reportedly effective in a variety of off-label applications, including some chronic pain conditions such as complex regional pain syndrome (formerly reflex sympathetic dystrophy syndrome) (Katznelson et al., 2016, Kiralp et al., 2004, Peach, 1995), fibromyalgia syndrome (Efrati et al., 2015, Yildiz et al., 2004), migraine or cluster headache (Di Sabato et al., 1993, Myers and Myers, 1995, Wilson et al., 1998), myofascial pain syndrome (Kiralp et al., 2009) and idiopathic trigeminal neuralgia (Gu et al., 2012). In the preclinical setting, HBO2 has been shown to produce long-lasting pain relief in experimental animals (Chung et al., 2010, Gibbons et al., 2013, Warren et al., 1979). However, the mechanism through which HBO2 produces these effects is not, at present, fully characterized. Research in our laboratory has focused on elucidating the mechanism of antinociceptive action of HBO2. We have reported that an 11-min HBO2 treatment significantly reduced glacial acetic acid-induced abdominal constrictions in mice, an animal model of acute pain (Ohgami et al., 2009, Quock et al., 2011). We also found that repeated daily 60-min HBO2 treatments for 4 days induced an unparalleled biphasic antinociceptive response that consisted of 1) an early phase that lasted at least 6 h after the HBO2 treatment before dissipating; and 2) a late phase that emerged about 18 h after the early phase and lasted for up to 3 weeks (Chung et al., 2010). The acute antinociceptive response of mice to HBO2 is dependent on nitric oxide (NO) (Ohgami et al., 2009). Centrally administered inhibitors of neuronal nitric oxide synthase (nNOS) and antagonists of opioid receptors are able to block HBO2-induced antinociception in both acute and long-lasting antinociceptive models, indicating a centrally active pathway mediating HBO2-induced antinociception (Chung et al., 2010, Gibbons et al., 2013, Ohgami et al., 2009, Quock et al., 2011, Zelinski et al., 2009). NO can act as a signaling molecule in the CNS and is associated with diverse behaviors including learning, memory and sleeping, as well as sensory and motor function (Garthwaite, 2008). NO has also been shown to function similarly to a neurotransmitter in the CNS depending upon the circuit (Garthwaite, 2008). NO may be produced both pre- and post-synaptically and has been shown to both depolarize and hyperpolarize nerve cells (Garthwaite, 2008). Finally, NO can act as both a neurotransmitter and a neuromodulator by modulating the release of several other neurotransmitters, including GABA (Kuriyama and Ohkuma, 1995). γ-Aminobutyric acid (GABA) neurons are widely distributed in the central nervous system, including supraspinal and spinal sites involved in transmission of afferent pain signals and descending pain-modulating pathways (Enna and McCarson, 2006). Drugs that activate GABA receptors have been found to produce antinociception in rodents (Krogsgaard-Larsen et al., 2004, Sawynok, 1987). Moreover, GABA receptors have been implicated in mediating stress-induced antinociception (Tokuyama et al., 1992) as well as the antinociceptive effects of drugs such as benzodiazepines (Kunchandy and Kulkarni, 1987), delta opioid peptides and heroin (Rady and Fujimoto, 1996, Rady and Fujimoto, 1995).