Hyperbaric Oxygen Treatment Induces a 2-Phase Antinociceptive Response of Unusually Long Duration in Mice


      Hyperbaric oxygen (HBO2) therapy is approved by the FDA for limited clinical indications but is reported to produce pain relief in several chronic pain conditions. However, there have been no studies to explain this apparent analgesic effect of HBO2. Research conducted in our laboratory demonstrates that 4 daily 60-minute HBO2 treatments at 3.5 absolute atmospheres induced an unparalleled antinociceptive response that consists of 1) an early phase that lasted at least 6 hours after the HBO2 treatment before dissipating; and 2) a late phase that emerged about 18 hours after the early phase and lasted for up to 3 weeks. The early phase was sensitive to antagonism by acutely intracerebroventricular (i.c.v.)-administered opioid antagonist naltrexone and the nitric oxide synthase (NOS)-inhibitor L-NAME. The late phase was inhibited by treatment with i.c.v. naltrexone or L-NAME during the 4 daily HBO2 treatments but was not antagonized by either naltrexone or L-NAME following acute pretreatment 2 weeks after HBO2 treatment. These experimental results implicate a novel mechanism that is activated by HBO2, resulting in an antinociceptive response of unusually long duration that is of potential interest in the clinical management of pain.


      Hyperbaric oxygen treatment of mice can induce a 2-phase antinociceptive response of unusually long duration. Nitric oxide and opioid receptors appear to initiate or mediate both phases of the antinociceptive response. Further elucidation of the underlying mechanism may potentially identify molecular targets that cause long-lasting activation of endogenous analgesic systems.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Bitterman N.
        • Bitterman H.
        L-arginine-NO pathway and CNS oxygen toxicity.
        J Appl Physiol. 1998; 84: 1633-1638
        • Chavko M.
        • Auker C.R.
        • McCarron R.M.
        Relationship between protein nitration and oxidation and development of hyperoxic seizures.
        Nitric Oxide. 2003; 9: 18-23
        • Chen Y.
        • Nadi N.S.
        • Chavko M.
        • Auker C.R.
        • McCarron R.M.
        Microarray analysis of gene expression in rat cortical neurons exposed to hyperbaric air and oxygen.
        Neurochem Res. 2009; 34: 1047-1056
        • Dall'Era M.A.
        • Hampson N.B.
        • Hsi R.A.
        • Madsen B.
        • Corman J.M.
        Hyperbaric oxygen therapy for radiation induced proctopathy in men treated for prostate cancer.
        J Urol. 2006; 176: 87-90
        • Demchenko I.T.
        • Boso A.E.
        • Whorton A.R.
        • Piantadosi C.A.
        Nitric oxide production is enhanced in rat brain before oxygen-induced convulsions.
        Brain Res. 2001; 917: 253-261
        • Di Sabato F.
        • Fusco B.M.
        • Pelaia P.
        • Giacovazzo M.
        Hyperbaric oxygen therapy in cluster headache.
        Pain. 1993; 52: 243-245
        • Elayan I.M.
        • Axley M.J.
        • Prasad P.V.
        • Ahlers S.T.
        • Auker C.R.
        Effect of hyperbaric oxygen treatment on nitric oxide and oxygen free radicals in rat brain.
        J Neurophysiol. 2000; 83: 2022-2029
        • Emmanouil D.E.
        • Dickens A.S.
        • Heckert R.W.
        • Ohgami Y.
        • Chung E.
        • Han S.
        • Quock R.M.
        Nitrous oxide-antinociception is mediated by opioid receptors and nitric oxide in the periaqueductal gray region of the brain.
        Eur Neuropsychopharmacol. 2008; 18: 194-199
      1. Feldmeier J.J. Hyperbaric Oxygen 2003 – Indications and Results. The UHMS Hyperbaric Oxygen Therapy Committee Report. Undersea and Hyperbaric Medical Society, Durham, NC2003
        • Haley T.J.
        • McCormick W.G.
        Pharmacological effects produced by intracerebral injections of drugs in the conscious mouse.
        Br J Pharmacol. 1957; 12: 12-15
        • Hirata T.
        • Cui Y.J.
        • Funakoshi T.
        • Mizukami Y.
        • Ishikawa Y.-I.
        • Shibasaki F.
        • Matsumoto M.
        • Sakabe T.
        The temporal profile of genomic responses and protein synthesis in ischemic tolerance of the rat brain induced by repeated hyperbaric oxygen.
        Brain Res. 2007; 1130: 214-222
        • Jain K.K.
        Physical, physiological, and biochemical aspects of hyperbaric oxygenation.
        in: Jain K.K. Textbook of Hyperbaric Medicine, (3rd ed.). Hogrefe and Huber Publishers, Seattle, WA1999: 11-27
        • Jones K.
        • Evans A.W.
        • Bristow R.G.
        • Levin W.
        Treatment of radiation proctitis with hyperbaric oxygen.
        Radiother Oncol. 2006; 78: 91-94
        • Kiralp M.Z.
        • Yildiz S.
        • Vural D.
        • Keskin I.
        • Ay H.
        • Dursun H.
        Effectiveness of hyperbaric oxygen therapy in the treatment of complex regional pain syndrome.
        J Int Med Res. 2004; 32: 258-262
        • Lee C.C.
        • Chen S.C.
        • Tsai S.C.
        • Wang B.W.
        • Liu Y.C.
        • Lee H.M.
        • Shyu K.G.
        Hyperbaric oxygen induces VEGF expression through ERK, JNK and c-Jun/AP-1 activation in human umbilical vein endothelial cells.
        J Biomed Sci. 2006; 13: 143-156
        • Liu W.
        • Li J.
        • Sun X.
        • Liu K.
        • Zhang J.H.
        • Xu W.
        • Tao H.
        Repetitive hyperbaric oxygen exposures enhance sensitivity to convulsion by upregulation of eNOS and nNOS.
        Brain Res. 2008; 1201: 128-134
        • Myers D.E.
        • Myers R.A.
        A preliminary report on hyperbaric oxygen in the relief of migraine headache.
        Headache. 1995; 35: 197-199
        • Nakabayashi M.
        • Beard C.
        • Kelly S.M.
        • Carr-Locke D.L.
        • Oh W.K.
        Treatment of a radiation-induced rectal ulcer with hyperbaric oxygen therapy in a man with prostate cancer.
        Urol Oncol. 2006; 24: 503-508
        • Ohgami Y.
        • Chung E.
        • Shirachi D.Y.
        • Quock R.M.
        Influence of hyperbaric oxygen on regional brain levels and spinal cord levels of nitric oxide metabolites in rat.
        Brain Res Bull. 2008; 75: 668-673
        • Ohgami Y.
        • Zylstra C.C.
        • Quock L.P.
        • Chung E.
        • Shirachi D.Y.
        • Quock R.M.
        Nitric oxide in hyperbaric oxygen-induced acute antinociception in mice.
        NeuroReport. 2009; 20: 1325-1329
        • Peach G.
        Hyperbaric oxygen and the reflex sympathetic dystrophy syndrome: a case report.
        Undersea Hyperb Med. 1995; 22: 407-408
        • Sümen G.
        Çimşit M, Eroğlu L: Hyperbaric oxygen treatment reduces carrageenan-induced acute inflammation in rats.
        Eur J Pharmacol. 2001; 431: 265-268
        • Takeyama N.
        • Sakai H.
        • Ohtake H.
        • Mashitori H.
        • Tamai K.
        • Saotome K.
        Effects of hyperbaric oxygen on gene expressions of procollagen, matrix metalloproteinase and tissue inhibitor of metalloproteinase in injured medial collateral ligament and anterior cruciate ligament.
        Knee Surg Sports Traumatol Arthrosc. 2007; 15: 443-452
        • Thom S.R.
        • Bhopale V.
        • Fisher D.
        • Manevich Y.
        • Huang P.L.
        • Buerk D.G.
        Stimulation of nitric oxide synthase in cerebral cortex due to elevated partial pressures of oxygen: An oxidative stress response.
        J Neurobiol. 2002; 51: 85-100
        • Tuter N.V.
        • Danilov A.B.
        • Poliakova L.V.
        The treatment of a complex regional pain syndrome. Zh Nevrol Psikhiatr Im S S Korsakova. 1997; 97: 33-35
        • Vingolo E.M.
        • Pelaia P.
        • Forte R.
        • Rocco M.
        • Giusti C.
        • Rispoli E.
        Does hyperbaric oxygen (HBO) delivery rescue retinal photoreceptors in retinitis pigmentosa?.
        Doc Ophthalmol. 1999; 97: 33-39
        • Vingolo E.M.
        • Rocco M.
        • Grenga P.
        • Salvatore S.
        • Pelaia P.
        Slowing the degenerative process, long lasting effect of hyperbaric oxygen therapy in retinitis pigmentosa.
        Graefes Arch Clin Exp Ophthalmol. 2008; 246: 93-98
        • Warren J.
        • Sacksteder M.R.
        • Thuning C.A.
        Therapeutic effect of prolonged hyperbaric oxygen in adjuvant arthritis of the rat.
        Arthritis Rheum. 1979; 22: 334-339
        • Wilson H.D.
        • Toepfer V.E.
        • Senapati A.K.
        • Wilson J.R.
        • Fuchs P.N.
        Hyperbaric oxygen treatment is comparable to acetylsalicylic acid treatment in an animal model of arthritis.
        J Pain. 2007; 8: 924-930
        • Wilson H.D.
        • Wilson J.R.
        • Fuchs P.N.
        Hyperbaric oxygen treatment decreases inflammation and mechanical hypersensitivity in an animal model of inflammatory pain.
        Brain Res. 2006; 1098: 126-128
        • Wilson J.R.
        • Foresman B.H.
        • Gamber R.G.
        • Wright T.
        Hyperbaric oxygen in the treatment of migraine with aura.
        Headache. 1998; 38: 112-115
        • Yildiz S.
        • Kiralp M.Z.
        • Akin A.
        • Keskin I.
        • Ay H.
        • Dursun H.
        • Cimsit M.
        A new treatment modality for fibromyalgia syndrome: Hyperbaric oxygen therapy.
        J Int Med Res. 2004; 32: 263-267
        • Zelinski L.M.
        • Ohgami Y.
        • Chung E.
        • Shirachi D.Y.
        • Quock R.M.
        A prolonged NO-dependent, opioid-mediated antinociceptive effect of hyperbaric oxygen in mice.
        J Pain. 2009; 10: 167-172