Endoplasmic reticulum stress contributes to high-dose radiation-induced chronic mechanical and thermal neuropathic pain.

IntroductionExposure to high doses of radiation can cause serious harm to human health and lead to long-term chronic pain. However, the mechanisms underlying pain caused by radiation overexposure remain largely unknown.MethodsIn this study, the double hind paws and tail of mice were exposed to 40Gy electron beams to establish a radiation-induced pain model.ResultsEven after the inflammation of the irradiated skin subsided, the mice continued to exhibit prolonged mechanical and thermal pain. The results indicated that the neuron injury marker activating transcription factor 3 (ATF3) was markedly increased and neuronal excitability was significantly increased 1 month post-radiation in the lumbar dorsal root ganglion (DRG). Yet, radiation-induced chronic pain could not be mitigated by common analgesics. We discovered that endoplasmic reticulum (ER) stress was activated in the DRG, and intraperitoneal injections of the ER stress antagonists 4-phenylbutyric acid (4-PBA) and TUDCA significantly alleviated mechanical and thermal allodynia. Additionally, 4-PBA and TUDCA reduced the neuronal hyperexcitability caused by radiation. Moreover, 4-PBA also ameliorated the motor dysfunction induced by high-dose radiation.InterpretationOur findings highlight the pivotal role of ER stress activation in the development of chronic neuropathic pain induced by high doses of radiation. Furthermore, our findings suggest that targeting ER stress may offer a promising approach for preventing chronic abnormal pain resulting from high doses of radiation.