Antinociception and neuroprotection of the peptidic G protein‐coupled estrogen receptor inverse agonist PLMI in the murine model of paclitaxel‐induced peripheral neuropathy

BACKGROUND AND PURPOSE: The G protein-coupled estrogen receptor (GPER) participates in nociception. The GPER inverse agonist, a tetrapeptide (PLMI), was studied on pain-like symptoms, in murine models of chemotherapy-induced peripheral neuropathy. EXPERIMENTAL APPROACH: All experiments were performed in mice. We used the PLMI and the GPER antagonist G15 to study the role of GPER in mechanical allodynia in the model of paclitaxel-induced peripheral neuropathy. Sites of GPER/PLMI actions were explored by using nociceptors and dorsal horn GPER knockouts. The effect of PLMI and/or G15 was assessed in dorsal root ganglia primary cultures to explore the role of GPER in neuronal calcium flux. After a chronic administration of PLMI, the antinociceptive and neuroprotective effects were investigated in the paclitaxel-induced neuropathy model. Short term memory, reward-related conditioning and acute effects in bortezomib- and oxaliplatin-induced nociception were evaluated. NMR and CD spectroscopy were used to determine the conformation of the peptide PLMI, in solution. KEY RESULTS: In our paclitaxel-induced pain-like symptoms model, peripheral, spinal and supraspinal GPER participates in nociception. The peptide PLMI decreases nociception by lowering intraneuronal free calcium flux. Chronic PLMI treatment reduces pain-like behaviours and protects against nerve conduction velocity deficits, without causing cognitive impairments or addiction. PLMI alleviates oxaliplatin- and bortezomib-induced neuropathic pain. The peptide PLMI adopts a turn conformation. CONCLUSION AND IMPLICATIONS: Our results suggest that GPER inverse agonists could be used to alleviate nociception and to protect against paclitaxel-induced peripheral neuropathy. The turn conformation of the PLMI peptide in solution is in favour of a bioactive GPCR-interacting peptide.