Targeting Circadian Rhythm to Treat Cancer Pain

Nearly half of cancer patients experience pain that severely reduces their quality of life (Snijders et al., 2023). Pain associated with cancer can be caused by several factors, from tumors compressing the nerves to chemotherapy agents. Depending on the origin and structures involved, cancer-related pain is frequently classified as nociceptive (affecting somatic or visceral structures), neuropathic (affecting somatosensory systems), and mixed. Neuropathic pain accounts for 40% of cancer pain, with patients commonly describing sensory abnormalities such as pain to innocuous stimuli (allodynia) and heightened pain to noxious stimuli (hyperalgesia; Yoon and Oh, 2018). Neuropathic cancer pain can be unresponsive to opioids and other similar therapeutic options, highlighting the need to understand the underlying mechanisms for designing treatment strategies (Yoon and Oh, 2018). Past research has uncovered several molecular and cellular factors that might be associated with neuropathic pain. During normal conditions, information regarding innocuous and noxious stimuli is processed by complex spinal horn circuits that propagate the appropriate signals to the brain. However, abnormalities in this process can lead to allodynia and other pain-related symptoms (reviewed in Inoue and Tsuda, 2018). Additionally, non-neuronal cells such as astrocytes and microglia can exacerbate the sensation of pain. For instance, activation of spinal glia, which results in morphological and transcriptional changes, is associated with neuropathic pain. Spinal glia might display abnormal expression of diverse factors including interferon regulatory factor 8, purinergic receptors, bone-derived neurotropic factors, potassium/chloride cotransporters, cytokines, and several others that can contribute to pain hypersensitivity (Inoue and Tsuda, 2018). An additional layer of complexity of pain in cancer stems from the diurnal pattern of pain perception, with studies reporting heightened cancer-associated pain in patients during the day (Campagna et al., 2018). Circadian clock genes are likely playing a role in regulating this diurnal … Correspondence should be addressed to Niveditha Sankar at nsankar{at}unmc.edu.