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.

Sigma-1 Receptor Agonism Promotes Mechanical Allodynia After Priming the Nociceptive System with Capsaicin

“…refs 8, 16 and 17), they are able to decrease the pain responses induced by chemical irritants such as formalin or capsaicin (e.g. refs 18, 19, 20) as well as the sensory gain (allodynia or hyperalgesia) occurring due to sensitization of the nociceptive system by capsaicin81621 or by pathological states such as neuropathy, inflammation or ischemic pain817222324.…”

Transmission pathways and mediators as the basis for clinical pharmacology of pain

“…The σ1R has been demonstrated to play a role in the sensitivity of both acute and chronic pain, with σ1R knockout mice showing decreased pain responses [190]. Currently, a σ1R antagonist is in phase II clinical trials for neuropathic pain.…”

“…Currently, a σ1R antagonist is in phase II clinical trials for neuropathic pain. Early studies support a potential role for the use of σ1R antagonists in the treatment of chronic neuropathic pain [190]. …”

Sigma 2 Receptor/Tmem97 Agonists Produce Long Lasting Antineuropathic Pain Effects in Mice

“…3 The involvement of this receptor in pain signaling has been studied extensively, and a variety of compounds that bind to σ 1R demonstrate antinociceptive effects. 4 E-52862, 5 a σ 1R antagonist, is currently in phase II clinical trials for the treatment of neuropathic pain as both a monotherapy and in a multidrug cocktail.…”