Adenosine signaling mediate pain transmission in the central nervous system

Pain is a common clinical symptom that seriously affects the quality of life in a variety of patient populations. In recent years, research on the role of adenosine signaling in pain modulation has made great progress. Adenosine is a purine nucleoside and a neuromodulator, and regulates multiple physiological and pathophysiological functions through the activation of four G protein-coupled receptors, which are classified as A₁, A_2A, A_2B, and A₃ adenosine receptors (ARs). Adenosine and its receptors that are widespread in the central nervous system (CNS) play an important role in the processing of nociceptive sensory signals in different pain models. A₁Rs have the highest affinity to adenosine, and the role in analgesia has been well investigated. The roles of A_2ARs and A_2BRs in the modulation of pain are controversial because they have both analgesic and pronociceptive effects. The analgesic effects of A₃Rs are primarily manifested in neuropathic pain. In this article, we have reviewed the recent studies on ARs in the modulation of neuropathic pain, inflammatory pain, postoperative pain, and visceral pain in the CNS. Furthermore, we have outlined the pathways through which ARs contribute to pain regulation, thereby shedding light on how this mechanism can be targeted to provide effective pain relief.