Targeting TRPV1 for Cancer Pain Relief: Can It Work?

Simple Summary Medical control of cancer pain is often unsatisfactory. Narcotic drugs (opioids) are effective pain killers, but they have important negative effects on the central nervous system and the are also highly addictive. A logical strategy to avoid central narcotic adverse effects is to target the peripheral nociceptors where cancer pain is generated. Sensory afferents that express the capsaicin receptor TRPV1 play a central role in cancer pain. In animal experiments, pharmacological blockade or chemical ablation of these nerves provide lasting cancer pain relief. High-dose capsaicin patches are already in clinical use in patients with chemotherapy-induced neuropathic pain. Site-specific resiniferatoxin (an ultrapotent capsaicin analog) injections are currectly undergoing clinical trials in patients with chronic intractable cancer pain caused by metastatic bone disease. This review explores the analgesic potential of small molecule TRPV1 antagonists and the sensory afferent desensitization in cancer patients.Abstract Chronic intractable pain affects a large proportion of cancer patients, especially those with metastatic bone disease. Blocking sensory afferents for cancer pain relief represents an attractive alternative to opioids and other drugs acting in the CNS in that sensory nerve blockers are not addictive and do not affect the mental state of the patient. A distinct subpopulation of sensory afferents expresses the capsaicin receptor TRPV1. Intrathecal resiniferatoxin, an ultrapotent capsaicin analog, ablates TRPV1-expressing nerve endings exposed to the cerebrospinal fluid, resulting in permanent analgesia in women with cervical cancer metastasis to the pelvic bone. High-dose capsaicin patches are effective pain killers in patients with chemotherapy-induced peripheral neuropathic pain. However, large gaps remain in our knowledge since the mechanisms by which cancer activates TRPV1 are essentially unknown. Most important, it is not clear whether or not sensory denervation mediated by TRPV1 agonists affects cancer progression. In a murine model of breast cancer, capsaicin desensitization was reported to accelerate progression. By contrast, desensitization mediated by resiniferatoxin was found to block melanoma growth. These observations imply that TRPV1 blockade for pain relief may be indicated for some cancers and contraindicated for others. In this review, we explore the current state of this field and compare the analgesic potential of TRPV1 antagonism and sensory afferent desensitization in cancer patients.