Dose-Dependent Effect of Hyperbaric Oxygen Treatment on Burn-Induced Neuropathic Pain in Rats

Abstract

Hyperbaric oxygen treatment (HBOT) has been used to reduce neuropathic pain. Melatonin and opioid receptors are involved in neuropathic pain, but it is not known if HBOT works through these pathways to achieve its antinociceptive effect. We divided anesthetized rats into two treatment and three sham groups. The two treatment groups received third-degree burns on their right hind paws, one treated in a hyperbaric chamber for a week and the other for two weeks. We evaluated the mechanical paw-withdrawal threshold (MWT) and expression of melatonin receptor 1 (MT1), melatonin receptor 2 (MT2), μ (MOR) and κ (KOR) opioid receptor, brain-derived neurotrophic factor (BDNF), Substance P, and calcitonin gene-related peptide (CGRP) in cuneate nucleus, dorsal horn, and hind paw skin by immunohistochemical, immunofluorescence assays and real-time quantitative polymerase chain reaction (RT-PCR). The group receiving one-week HBOT had increased expressions of MT1, MT2, MOR and KOR and decreased expressions of BDNF, Substance P, and CGRP. Their mechanically measured pain levels returned to normal within a week and lasted three weeks. This anti-allodynia effect lasted twice as long in those treated for two weeks. Our findings suggest that increasing the duration of HBOT can reduce burn-induced mechanical allodynia for an extended period of time in rats. The upregulation of melatonin and opioid receptors observed after one week of HBOT suggests they may be partly involved in attenuation of the mechanical allodynia. Downregulation of BDNF, substance P and CGRP may have also contributed to the overall beneficial effect of HBOT.

The History and Development of Hyperbaric Oxygenation (HBO) in Thermal Burn Injury

“…Again, all studies were done in rodents, and all but one [ 62 ] in rats. The investigators set their focuses on intestinal bacteria [ 63 ], prevention of inflammation and necrosis as well as on regeneration [ 62 , 64 , 65 , 66 ] and on alleviation of pain [ 67 , 68 ] induced by burn injury. The maximum pressure applied was 2.5 ATA.…”

“…In a recent study, in 2019, he was able to show, that HBO reduced burn-induced mechanical allodynia, in correlation to the duration of treatment. The effect was accompanied by an upregulation of melatonin and opioid receptors, and by downregulation of brain derived neurotropic factor, substance P and calcitonin gene-related peptide [ 68 ].…”

“…Recent investigations focusing on postburn pain documented marked reduction of sensitation that could be induced by even one single HBO treatment session [ 27 , 28 , 34 , 67 , 68 ].…”

<p>Role of Melatonin in the Regulation of Pain</p>

“…Melatonin receptors in both central and peripheral nervous system have been considered antinociceptive, due to mounting evidence in many rodent models of neuropathic pain. 89,93,105,106 In rat L5-L6 SNL and spared nerve injury models, a selective MT2 partial agonist, UCM924, exerted anti-allodynic effects by modulating the ON/OFF cells of the antinociceptive system, suggesting that MT2 receptor may be an important target in analgesic drug development. 15 Meanwhile, in the hot-plate and formalin tests, UCM765 (another selective MT2 partial agonist) and UCM924 also exert an antinociceptive effect.…”

“…124,125 In agreement with these results, the overexpression of opioid receptors is observed after hyperbaric oxygen treatment of neuropathic pain, suggesting that the opiate system participates in attenuation of allodynia. 106 Piromelatine is effective in treating neuropathic pain and sleep disturbance in PSL rats mediated by opioid receptors. 93 Melatonin not only increased the pain threshold of mechanical allodynia but also enhanced the threshold of thermal hypersensitivity.…”