title: The selective sigma-1 receptor antagonist E-52862 attenuates neuropathic pain of different aetiology in rats.
abstract: E-52862 is a selective σ1R 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 σ1R in neuropathic pain and extend the potential for the use of selective σ1R antagonists (e.g., E-52862) to the chronic treatment of cephalic and extra-cephalic neuropathic pain.
authors.affiliation: Department of Pharmacology, Drug Discovery &Preclinical Development, ESTEVE, Barcelona, Spain.
authors.forename: Georgia
authors.initials: G
authors.lastname: Gris
authors.affiliation: Department of Pharmacology, Drug Discovery &Preclinical Development, ESTEVE, Barcelona, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Portillo-Salido
authors.affiliation: Department of Pharmacology, Drug Discovery &Preclinical Development, ESTEVE, Barcelona, Spain.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Aubel
authors.affiliation: ANS Biotech, RIOM Cedex, France.
authors.forename: Yassine
authors.initials: Y
authors.lastname: Darbaky
authors.affiliation: Laboratory of Anesthesiology, University of Antwerp, Antwerp, Belgium.
authors.forename: Kristof
authors.initials: K
authors.lastname: Deseure
authors.affiliation: Department of Pharmacology, Drug Discovery &Preclinical Development, ESTEVE, Barcelona, Spain.
authors.forename: José Miguel
authors.initials: JM
authors.lastname: Vela
authors.affiliation: Department of Pharmacology, Drug Discovery &Preclinical Development, ESTEVE, Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Merlos
authors.affiliation: Department of Pharmacology, Drug Discovery &Preclinical Development, ESTEVE, Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zamanillo
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D003929:Diabetic Neuropathies / Q000150:complications; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D009437:Neuralgia / Q000188:drug therapy* / Q000209:etiology; D009944:Organoplatinum Compounds / Q000633:toxicity; D000077150:Oxaliplatin; D059348:Peripheral Nerve Injuries / Q000150:complications; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D000097605:Sigma-1 Receptor
chemical_list: D000700:Analgesics; D009025:Morpholines; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D011720:Pyrazoles; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C576663:4-(2-((5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl)oxy)ethyl)morpholine