A TRPA1 antagonist reverts oxaliplatin-induced neuropathic pain

Abstract

Neuropathic pain (NeP) is generally considered an intractable problem, which becomes compelling in clinical practice when caused by highly effective chemotherapeutics, such as in the treatment of cancer with oxaliplatin (OXA) and related drugs. In the present work we describe a structurally new compound, ADM_09, which proved to effectively revert OXA-induced NeP in vivo in rats without eliciting the commonly observed negative side-effects. ADM_09 does not modify normal behavior in rats, does not show any toxicity toward astrocyte cell cultures, nor any significant cardiotoxicity. Patch-clamp recordings demonstrated that ADM_09 is an effective antagonist of the nociceptive sensor channel TRPA1, which persistently blocks mouse as well as human variants of TRPA1. A dual-binding mode of action has been proposed for ADM_09, in which a synergic combination of calcium-mediated binding of the carnosine residue and disulphide-bridge-forming of the lipoic acid residue accounts for the observed persistent blocking activity toward the TRPA1 channel.

RETRACTED ARTICLE: Auraptenol attenuates vincristine-induced mechanical hyperalgesia through serotonin 5-HT1A receptors

“…In an effort to better understand this form of neuropathy and develop novel treatment for its management, several animal models of chemotherapeutic agent-induced neuropathy was developed101112. Rodents treated with chemotherapeutic agents typically develop thermal and mechanical hyperalgesia.…”

Intrathecal administration of nociceptin/orphanin FQ receptor agonists in rats: A strategy to relieve chemotherapy-induced neuropathic hypersensitivity

“…was ineffective in a rat model of paclitaxel-induced pain whereas 8 mg/kg reduced pain by about 50% (Dellmijn, 1999). On the other hand, pathophysiological mechanisms of neuropathy may negatively modulate the analgesic effect of systemic opioid by receptor signal alteration of the descending system (Leighton et al, 1988) as well as by maladaptive tissue plasticity (Di Cesare Mannelli et al, 2014a;Di Cesare Mannelli et al, 2014b;Nativi et al, 2013;Scholz and Woolf, 2007;Song and Zhao, 2001;Watkins et al, 2005).…”

Ion channels in nociceptors

“…[75][76][77][78] Experimental models show that TRPA1, which is sensitive to products of oxidative and nitrosative stress, contributes to different types of inflammatory and neuropathic pain. For example, TRPV1 and TRPA1 are involved in thermal hyperalgesia induced by cisplatinum 74 ; TRPA1 and TMP8 mediate pain and cold allodynia induced by oxaliplatin.…”