title: Sigma-1 receptors and animal studies centered on pain and analgesia.
abstract: BACKGROUND
  Neuropathic pain is difficult to relieve with standard analgesics and tends to be resistant to opioid therapy. Sigma-1 receptors activated during neuropathic injury may sustain pain. Neuropathic injury activates sigma-1 receptors, which results in activation of various kinases, modulates the activity of multiple ion channels, ligand activated ion channels and voltage-gated ion channels; alters monoamine neurotransmission and dampens opioid receptors G-protein activation. Activation of sigma-1 receptors tonically inhibits opioid receptor G-protein activation and thus dampens analgesic responses. Therefore, sigma-1 receptor antagonists are potential analgesics for neuropathic and adjuvants to opioid therapy.
  
  
  METHODS
  This article reviews the importance of sigma-1 receptors as pain generators in multiple animal models in order to illustrate both the importance of these unique receptors in pathologic pain and the potential benefits to sigma-1 receptor antagonists as analgesics.
  
  
  CONCLUSIONS
  Sigma-1 receptor antagonists have a great potential as analgesics for acute neuropathic injury (herpes zoster, acute postoperative pain and chemotherapy induced neuropathy) and may, as an additional benefit, prevent the development of chronic neuropathic pain. Antagonists are potentially effective as adjuvants to opioid therapy when used early to prevent analgesic tolerance. Drug development is complicated by the complexity of sigma-1 receptor pharmacodynamics and its multiple targets, the lack of a specific sigma-1 receptor antagonist, and potential side effects due to on-target toxicities (cognitive impairment, depression).
authors.affiliation: Case Western Reserve University, Taussig Cancer Institute, Cleveland Clinic Lerner School of Medicine, Palliative Medicine and Supportive Oncology Services, Division of Solid Tumor, The Cleveland Clinic , 9500 Euclid Ave, Cleveland, OH 44195 , USA davism6@ccf.org.
authors.forename: Mellar P
authors.initials: MP
authors.lastname: Davis
mesh_terms: D000700:Analgesics / Q000009:adverse effects / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D015195:Drug Design; D004361:Drug Tolerance; D006801:Humans; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology; D017480:Receptors, sigma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D000700:Analgesics; D000701:Analgesics, Opioid; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor
keywords: agonist; analgesia; antagonist; pain; receptor; sigma