Adenosine Metabotropic Receptors in Chronic Pain Management

The pharmacological treatment of chronic pain is still unsatisfactory. The cellular and molecular mechanisms at the basis of pain chronification are still poorly understood. The commercially available drugs for treating chronic pain, including neuropathic pain, are effective in few patients and own several side effects that often limit the compliance of the patients. In addition, the opioids, which are the most potent analgesics, often fail in chronic pain conditions, especially in neuropathic pain syndromes. Moreover, it is well known that opiates can lead to addiction, tolerance and hyperalgesia. Therefore, new targets for treating neuropathic pain are needed. Purines, including ATP, ADP and adenosine and their receptors are deeply involved in the pathophysiology of neuropathic pain, particularly in the immune-mediated reactions that are responsible for the induction of the tactile allodynia, that represents the main symptom of neuropathic pain. The first response to the insult is mediated by the production of ATP and the activation of P2X receptors (Jacobson et al., 2020). In particular, the P2X4 receptors on microglia have been identified to be essential for the involvement of microglia cells in the pain pathophysiology (Trang et al., 2012). Beside the P2X, the P2Y receptors tend to boost the immune cells in response to nucleotides, with their ligands acting as immediate danger signals (Cekic and Linden, 2016). The subsequent stimulation of the metabotropic P1 adenosine receptors (ARs), of which are known four subtypes (A1, A2A, A2B, and A3), is overall associated with the reduction of both immunoinflammatory response and pain (Vincenzi et al., 2020). In the present opinion paper we will focus on the role of the P1 adenosine receptors in the pathophysiology of chronic neuropathic pain. The involvement of P2X and P2Y receptors in chronic pain has been discussed elsewhere (Jacobson et al., 2020).