Emerging roles of the P2X7 receptor in cancer pain

Purinergic Signalling https://doi.org/10.1007/s11302-022-09902-1 REVIEW ARTICLE Emerging roles of the P2X7 receptor in cancer pain Ping Wu1 · Yin Wang2 · Yansong Liu2 · Yan Liu2 · Guohua Zhou3 · Xiaoqi Wu1 · Qingping Wen1 Received: 25 April 2022 / Accepted: 3 October 2022 © The Author(s) 2022 Abstract Cancer pain is the most prevalent symptom experienced by cancer patients. It substantially impacts a patient’s long-term physical and emotional health, making it a pressing issue that must be addressed. Purinergic receptor P2X7 (P2X7R) is a widely distributed and potent non-selective ATP-gated ion channel that regulates tumor proliferation, chronic pain, and the formation of inflammatory lesions in the central nervous system. P2X7R plays an essential role in cancer pain and complications related to cancer pain including depression and opioid tolerance. This review focuses on the structure and distribution of P2X7R, its role in diverse tissues in cancer pain, and the application of P2X7R antagonists in the treatment of cancer pain to propose new ideas for cancer pain management. Keywords P2X7 receptor · Cancer pain · Depression · P2X7 receptor antagonist Ping Wu graduated from Harbin Medical University with a master’s degree in anesthesiology. She is currently pursuing her Ph.D. in Anesthesiology at Dalian Medical University, focusing on the role of microglia polarization in cancer-induced bone pain and the role of P2X7 receptors in regulating M1 to M2 polarization. She is passionate about improving the treatment options available to treat cancer pain and hopes to continue research in this field after completing her Ph.D. Ping Wu and Yin Wang contributed equally to this study. * Qingping Wen Guohua Zhou Ping Wu Xiaoqi Wu Yin Wang 1 Yansong Liu Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China 2 Yan Liu Anesthesiology Department, Dalian Medical University, Dalian 116044, China 3 Ningbo First Hospital, Ningbo, China 13 Vol.:(0123456789) Purinergic Signalling Introduction Cancer incidence and mortality rates are on the rise with population size growth, increasing aging population, and the prevalence of cancer-causing factors [1]. Cancer pain is unavoidable for patients suffering from intermediate to advanced cancer [2]. Currently, most analgesics for cancer pain follow the international three-step analgesic protocol, which begins with non-steroidal anti-inflammatory drugs (NSAIDs) and transitions to NSAIDs plus mild opioids. Finally, when the pain becomes unbearable, potent opioids are used, supplemented by other treatments including radiation therapy, nerve blocks, antiepileptics, antidepressants, and steroids [3]. A systematic review of the literature on pain in cancer patients conducted over the last 40 years revealed that, on average, 53% of cancer patients report pain, with this percentage rising to 59% in patients receiving anti-cancer treatment and 33% still experiencing pain even after cured treatment [4]. Cancer pain is chronic pain with complex and distinct mechanisms, overlapping but not identical characteristics of inflammatory and neuropathic pain [5]. Sensitizing mediators produced and secreted by tumors and associated immune cells activate peripheral injurious receptors, which travel up to the dorsal root ganglion (DRG) or trigeminal ganglion (TG), which in turn establish synapses with second-order Fig. 1  Research status of P2X7R in the mechanism of cancer pain 13 interneurons in the dorsal horn of the spinal cord, activating spinal microglia to release inflammatory mediators [6]. These microglia interact with T cells that infiltrate the dorsal horn of the spinal cord after nerve injury and are involved in central sensitization and chronic pain [7]. Thus, due to the increased concentration of neuromodulators such as interleukin (IL)-1β, brain-derived cell growth factor (BDNF), and prostaglandin E2 in the cerebrospinal fluid, they can fine-tune excitatory or inhibitory synaptic transmission, ultimately enhancing the transmission of pain signals to the brain [8]. A large body of evidence suggests that P2X7R is a trigger for inflammatory factors and is widely distributed in tumor cells and various immune cells [9]. P2X7R can be activated by high ATP concentrations and mediates inflammatory responses by releasing pro-inflammatory cytokines such as tumor necrosis factor-α and IL-1β and activating various ion channels, G protein-coupled receptors, and tyrosine kinase receptors, thereby enhancing pain transduction and transmission [10, 11]. Significant progress has recently been made in investigating P2X7R to treat cancer pain. Moreover, many studies have revealed that negative emotions aggravate cancer pain progression, reduce patient compliance, and negatively affect cancer pain treatment [12]. The study of P2X7R in cancer pain has made significant progress in recent years, and it is likely to be an essential direction for cancer pain treatment in the future (Fig. 1). Purinergic Signalling Necrotic cells and activated immune cells release a large amount of ATP during cancer pain progression, which stimulates P2X7R-expressing macrophages, Schwann cells, and cancer cells to release pro-inflammatory factors and activate nociceptors directly. The pain signal is then transmitted to the dorsal root ganglion and cooperates with T cells to regulate neuronal plasticity and participate in central sensitization. Cells such as microglia and astrocytes that express P2X7Rs are activated at the spinal cord level, mediate inflammatory responses, and secrete neuromodulators. Finally, the pain signal is further enhanced and sent to the brain, where it produces pain sensations. P2X7R structure and distribution The P2 receptor family is divided into ligand-gated ion channel P2X receptors and G protein-coupled metabolic P2Y receptors [13]. P2X is an ATP-dependent non-selective cation channel purinoceptor, and up till now, seven P2X receptors (P2X1-7) have been cloned [14]. P2X7R has a lower affinity for ATP than other P2X receptor subtypes and is not activated at normal physiological concentrations; however, when dead cells and activated immune cells are in a state of inflammation or ischemic tissue injury, they release high concentrations of ATP (> 100 µmol/L) [15]; P2X7R is activated and other forms of cation-selective channels a2+ influx and K + efflux, resulting in that mediate N a+ and C changes in cellular ion homeostasis [16, 17]. Structurally, in contrast to other P2X receptors, P2X7R has a very long intracellular C-terminus that accounts for 40% of the entire protein, which is thought to be the primary reason for its physiological functions [18]. P2X7R is widely distributed in many cell types, including (i) almost all immune cells, including dendritic cells, macrophages, monocytes, granulocytes, lymphocytes, osteoblasts, osteoclasts, and osteocytes; (ii) neural cells, such as c (...truncated)