The Emerging Role of Sigma Receptors in Pain Medicine

Sigma receptors are protein chaperones with the unexpected characteristic of being activated by ligand binding. As such, they represent intriguing new targets for potential drug development. As a protein chaperone, these "receptors" escort proteins from the endoplasmic reticulum to their destinations and act to correct misfolded proteins. The two subtypes of sigma receptors, named σ1 and σ2, are markedly distinct from each other. Agonists and antagonists at these receptors show promise as new drug targets, addressing a range of diseases including neurodegenerative disorders, cancer, and cardiac disorders, and may also be analgesic agents and rehabilitation drugs for opioid use disorder. As an analgesic, sigma receptors seem to be more effective in treating neuropathic than nociceptive pain. New bifunctional compounds are being developed with opioids, because agents targeting sigma receptors may have an opioid-sparing effect. The pipeline of agents based on the sigma receptors is long and may treat things from Fragile X syndrome to Parkinson's disease to Huntington's disease to cancer. A novel agent ADV502 acts as a high-affinity σ1 antagonist and partial agonist at the µ-opioid receptor and may be an important agent both for the treatment of neuropathic cancer pain and for rehabilitation of opioid use disorder. Since there has been little recent innovation in pain medicine regarding new compounds and drug targets, drugs that affect the sigma receptor system seem promising and encouraging.