Hyperbaric Oxygen Attenuates Chronic Postsurgical Pain by Regulating the CD73/Adenosine/A1R Axis of the Spinal Cord in Rats

Abstract

Chronic postsurgical pain (CPSP) affects postoperative rehabilitation and quality of life in patients, but its mechanisms are still poorly understood. Hyperbaric oxygen (HBO) attenuates neuropathic pain in animal and human studies, but its efficacy for CPSP treatment and its underlying mechanism have not been elucidated. This study aimed to investigate the analgesic effect of HBO in a CPSP rat model and the role of spinal cord adenosine circulation in HBO-induced analgesia. A skin/muscle incision and retraction (SMIR) rat model was used to mimic CPSP, and HBO treatment (2.5 atmospheric absolute, 60 minutes) was administered once daily for 5 consecutive days beginning 3 days after surgery. The role of spinal cord adenosine circulation in HBO-induced analgesia was investigated using β-methylene ADP (a CD73 inhibitor), 8-cyclopentyl-1,3-dipropylxanthine (an A1R antagonist), or an intrathecal injection of adenosine. The mechanical paw withdrawal threshold was determined at different timepoints before and after surgery. The spinal cord adenosine and adenosine triphosphate (ATP) contents were analyzed using high-performance liquid chromatography, and the spinal cord expression of adenosine-1 receptor (A1R), extracellular 5′-nucleotidase (CD73), and adenosine kinase (ADK) was examined by Western blotting and immunofluorescence staining. The results showed that the mechanical paw withdrawal threshold of the ipsilateral hind paw and the adenosine content decreased, and the spinal cord expression of A1R, CD73, and ADK and ATP content increased within 14 days after surgery. HBO treatment alleviated mechanical allodynia, reduced ATP content, and increased adenosine content by activating CD73 but downregulated the spinal cord expression of A1R, CD73, and ADK. Intrathecal adenosine alleviated mechanical allodynia after SMIR and downregulated the spinal cord expression of A1R and CD73, and intrathecal β-methylene ADP or 8-cyclopentyl-1,3-dipropylxanthine attenuated the analgesic effect of HBO treatment on SMIR-induced CPSP. PerspectiveSpinal cord adenosine is involved in the occurrence and development of CPSP, and HBO treatment alleviates CPSP by regulating adenosine production/metabolism in the spinal cord. Thus, HBO may be employed for the treatment of CPSP with favorable efficacy.