The selective sigma-1 receptor antagonist E-52862 attenuates neuropathic pain of different aetiology in rats

• Published in: Scientific reports Vol. 6; no. 1; p. 24591
• Main Authors: Gris, Georgia, Portillo-Salido, Enrique, Aubel, Bertrand, Darbaky, Yassine, Deseure, Kristof, Vela, José Miguel, Merlos, Manuel, Zamanillo, Daniel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18-04-2016; Nature Publishing Group
• Subjects: 631/154/436/2387; 631/378/1689/2610; Analgesics; Analgesics - administration & dosage; Analgesics - pharmacology; Analgesics - therapeutic use; Animals; Antagonists; Clinical trials; Cold stimuli; Diabetes mellitus; Diabetic Neuropathies - complications; Diabetic neuropathy; Gabapentin; Humanities and Social Sciences; Hyperalgesia; Hyperalgesia - drug therapy; Hyperalgesia - etiology; Hypersensitivity; Male; Morphine; Morpholines - administration & dosage; Morpholines - pharmacology; Morpholines - therapeutic use; multidisciplinary; Neuralgia - drug therapy; Neuralgia - etiology; Organoplatinum Compounds - toxicity; Oxaliplatin; Pain; Pain perception; Peripheral Nerve Injuries - complications; Pharmacodynamics; Polyneuropathy; Pyrazoles - administration & dosage; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Rats; Rats, Sprague-Dawley; Receptors, sigma - antagonists & inhibitors; Rodents; Science; Sigma-1 Receptor; Streptozocin; Surgery
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep24591

E-52862 is a selective σ
1
R antagonist currently undergoing phase II clinical trials for neuropathic pain and represents a potential first-in-class analgesic. Here, we investigated the effect of single and repeated administration of E-52862 on different pain-related behaviours in several neuropathic pain models in rats: mechanical allodynia in cephalic (trigeminal) neuropathic pain following chronic constriction injury of the infraorbital nerve (IoN), mechanical hyperalgesia in streptozotocin (STZ)-induced diabetic polyneuropathy and cold allodynia in oxaliplatin (OX)-induced polyneuropathy. Mechanical hypersensitivity induced after IoN surgery or STZ administration was reduced by acute treatment with E-52862 and morphine, but not by pregabalin. In the OX model, single administration of E-52862 reversed the hypersensitivity to cold stimuli similarly to 100 mg/kg of gabapentin. Interestingly, repeated E-52862 administration twice daily over 7 days did not induce pharmacodynamic tolerance but an increased antinociceptive effect in all three models. Additionally, as shown in the STZ and OX models, repeated daily treatment with E-52862 attenuated baseline pain behaviours, which supports a sustained modifying effect on underlying pain-generating mechanisms. These preclinical findings support a role for σ
1
R in neuropathic pain and extend the potential for the use of selective σ
1
R antagonists (e.g., E-52862) to the chronic treatment of cephalic and extra-cephalic neuropathic pain.