Feasibility Study Of Hyperbaric Oxygen Treatment For Neuropathic Pain

The pathogenesis and treatment of neuropathic pain is one of the mostchallenging problems in medicine and biology. Neuropathic pain affectsapproximately6%to8%of the general population. People with neuropathicpain often live with low health-related quality of life. However, the currenttherapy for neuropathic pain is not satisfactory. Currently available drugs,including opioid, and various nondrug therapies offer very limited pain reliefclinically. More than two-thirds of neuropathic pain patients obtain insufficientpain relief. The International Study of Pain (IASP) pointed out that the clinicalchallenge is to identify and ameliorate the cause(s) of the pain.Based on our previous studies and reported evidence, we proposed that thesensory nerve injury may be the root cause of neuropathic pain. This viewcoincides with the changes in the field of neuropathic pain study. In2011, IASPreleased the new definition of neuropathic pain to replace the17-year olddefinition, which defined neuropathic pain as ‘‘NeuP is a pain arising as a direct consequence of a lesion or disease affecting the somatosensory system’.The majority of researchers believe that neuropathic pain is a maladaptiveresponse of the nervous system to damage. They believe that the initialetiological factor has been recovered by default, while almost completely ignorethe sensory nerve injury that induced neuropathic pain. The current situation ofpoor clinical outcomes reminds us that maybe these ideas are relativelyhomogeneous and one-sided. We focus on the fundamental causes and proposethat the neuroprotective means/drug treatments for sensory nerve injury mayalleviate pathological pain. This is a novel idea worth of exploring investigation.Hyperbaric oxygen (HBO) therapy has been clinically used for protection ofthe nervous system after acute injury. HBO treatment may attenuate injury tonerve tissues after stroke and hippocampus ischemia as well as improvingperipheral nerve repair and regeneration. We have demonstrated that HBOpreconditioning can induce tolerance against spinal cord ischemia. Recently,there are reports that HBO therapy appears to be effective in some chronic painconditions in patients such as headache and complex regional pain syndrome. Inexperimental animals, HBO treatment can attenuate inflammatory pain. Thesereports suggest a potential role of HBO in anti-nociception.We hypothesize that, as a therapy strategy, HBO, which can result in neuralprotection, might be effective in treating neuropathic pain through protecting theinjured nerves from further damage, and reversing or interrupting theinjury-induced processing of nociception.【Aims】The current studies were designed to investigate whether HBO treatmentcould attenuate neuropathic pain in CCI rats and to investigate the underlingmechanisms. 【Methods】HBO treatments (3ATA,100%O2) were administrated at different timepoints, early after nerve injury (within30min after CCI operation) or late afternerve injury (the14th day after CCI injury). Behavioral methods were used toexam the impact of HBO treatment on CCI rats. Neuropathic pain behaviormanifests as thermal hyperalgesia and mechanical allodynia. Thermalhyperalgesia was assessed by measuring foot withdrawal latency to heatstimulation. Mechanical allodynia was determined by measuring incidence offoot withdrawal in response to mechanical indentation of the plantar surface ofeach hind paw with Von Frey filaments. Immunofluorescence staining was usedto observe the state of c-fos expression and activation of astrocytes in superficialdorsal horn. The Western Blot method was used to detect pNR1, pNR2B,pCaMKII, pERK,pCREB and GFAP protein expression levels in rat spinal cord.【Results】Experiment one CCI produced rapid-onset and long-lasting thermalhyperalgesia and mechanical allodynia in rats. HBO treatment (3ATA, pureoxygen, starting~30min after surgery, once a day for7consecutive days)significantly reduced severity and shortened duration of thermal hyperalgesiaand mechanical allodynia. Within the first2weeks, latency of foot withdrawalrepresenting thermal sensitivity was reduced approximately70%(vs CCItreatment alone). In addition to decreasing severity of pain, HBO treatmentshortened duration of the thermal hyperalgesia to2weeks from at least5weeksin CCI rats. These results indicate that HBO therapy applied in the early phaseafter nerve injury can effectively attenuate severity and shorten duration ofneuropathic pain. Repetitive HBO treatment (3ATA, each60min), starting on thepostoperative day14, once a day for3consecutive days, produced a significant,transient inhibition of thermal hyperalgesia and mechanical allodynia. Inhibitionlasted for5-8days after termination of the last HBO treatment. Prolonged HBOtreatment in the same protocol for7consecutive days (during postoperative day14-20) produced long-lasting inhibition, which sustained the thermal andmechanical hypersensitivity at similar decreased levels for at least2weeks aftertermination of the last treatment. These results demonstrate that repetitive HBOtreatment is also effective in treating the well-developed, persistent pain andprolonged exposure to HBO may result in better treatment effects of theneuropathic pain symptoms.Experiment two CCI caused neurochemical alterations such as induction ofc-Fos in the DH ipsilateral to nerve injury, in addition to behavioral signs ofneuropathic pain. CCI-caused c-fos expression has a characteristic double-peakform. The first peak occurred at postoperative day3. After a transient decrease,the second peak occurred at postoperative day14-21.HBO treatment (3ATA)applied at the early phase (starting within30min after surgery, once a day for7consecutive days) or at the late phase (starting on14postoperative day, once aday for3consecutive days) significantly inhibited expression of c-Fos at thesecond peak, respectively.CCI also caused activation of astrocytes in the DH ipsilateral to nerveinjury. HBO treatment applied at the early phase (starting within30min aftersurgery, once a day for7consecutive days) significantly inhibited activation ofastrocytes on postoperative day14. Experiment three NMDA receptors and the subsequent Ca2+-dependentsignals have a well-developed role in neural plasticity and in various pain states.CCI significantly increased levels of pNR1, pNR2B, pERK, pCaMKII andpCREB detected on the14,28postoperative days. Repetitive HBO treatment atthe early phase significantly inhibited CCI-induced increased level of pNR2B,pERK and pCaMKII, but not the level of pNR1. Repetitive HBO treatment atthe early phase also significantly inhibited CCI-induced increased level ofpCREB on the postoperative day28.These results indicate that HBO treatmentcan efficiently reverse the increased neural activities and activities of NR2Breceptor and the subsequent Ca2+-dependent signals, while attenuatingbehavioral signs of neuropathic pain.Experiment four Peripheral nerve injury (CCI or SNL) decreased expressionof Sirt1in the DH ipsilateral to nerve injury. The expression Sirt1protein inspinal cord was decreased beginning at12h after peripheral nerve injury andremained at least for5days. Repetitive HBO treatment (3ATA, pure oxygen,starting~30min after surgery, once a day) significantly increased the expressionof SirT1protein on postoperative day5.【Conclusions】HBO is an effectve alternative therapy that markedly attenuatesneuropathic pain syndromes in animal model. HBO treatment in early phaseafter CCI produces a long-lasting inhibition of thermal hyperalgesia andmechanical allodynia, effectively attenuates severity and shortens duration ofneuropathic pain. Repetitive HBO treatment is also effective in treating thewell-developed, persistent pain and prolonged exposure to HBO may result inbetter treatment effects of the neuropathic pain symptoms. HBO treatment significantly inhibited the expression of c-Fos andactivation of astrocytes in the DH ipsilateral to nerve injury.HBO treatment can markedly suppress the nerve injury-induced increasedlevel of phosphorylation of NR2B, ERK, CaMKII and CREB. This suggests thatHBO therapy may also reduce neuropathic pain through inhibition of thesepain-signaling pathways.Peripheral nerve injury (CCI or SNL) decreased the expression of Sirt1inthe spinal cord ipsilateral to nerve injury. HBO treatment significantly increasedthe expression of Sirt1protein. Sirt1may be involved in the analgesicmechanism of HBO, but further research is needed.