Background & Aims
Paclitaxel, a key anticancer agent for triple-negative breast cancer (TNBC), induces persistent neuropathic pain, a side effect enduring years post-treatment. Current approaches lack efficacy, emphasizing the urgency for novel therapeutics. Our recent studies have highlighted the potential of modulating the G protein-coupled estrogen receptor (GPER) not only in controlling the growth of TNBC but also in managing inflammatory pain. Derived from the hinge region of the human ER?, the peptide PLMI has been identified as an inverse agonist of GPER. Its apoptotic and anti-proliferative actions on triple-negative breast cancer cells make it a promising molecule. Moreover, owing to its analgesic efficacy in managing inflammatory pain, the use of PLMI in the treatment of paclitaxel-induced neuropathic pain emerges as a promising solution. Here, we propose to perform a functional study investigating the analgesic effects of PLMI on a murine model of paclitaxel-induced neuropathic pain.
Methods
To induce peripheral neuropathies, 10-week-old female C57Bl6/j mice were used. Four injections of paclitaxel (4 mg/kg, i.p.) were administered on alternate days. Fourteen days post-initial paclitaxel administration, PLMI (GPER inverse agonist), G15 (GPER antagonist) or duloxetine was administered via intraperitoneal routes to assess GPER dependency of PLMI’s effect. Additionally, intraplantar, intrathecal, and intracerebroventricular routes were employed to elucidate the functional localization of its analgesic effect. The von Frey hair test was conducted at various time intervals post-treatment to assess mechanical allodynia.
Results
Our findings reveal that PLMI, in contrast to G15, exhibited a dose-dependent antinociceptive effect upon systemic administration. Additionally, this effect is abolished when PLMI was co-administered with G15 intraperitoneally. Similarly, the antinociceptive effect of PLMI, whether administered intraplantar, intrathecally or intracerebroventricularly, was entirely reversed upon concurrent G15 administration through the same route. Lastly, a fraction of the intraperitoneally administered PLMI’s antinociceptive effect was suppressed when GPER was blocked through intraplantar or intrathecal G15 administration, and completely abolished when G15 was administered intracerebroventricularly.
Conclusions
Our study reveals that the GPER inverse agonist, PLMI, induces a GPER-dependent antinociceptive effect in paclitaxel-induced neuropathic pain. Importantly, this effect is located across all levels of pain integration, encompassing peripheral, spinal and supraspinal modalities. Moreover, our data suggests the potential blood-brain barrier permeability of PLMI. Collectively, these findings highlight the promising therapeutic approach of GPER modulation through inverse agonists for addressing both TNBC tumors and paclitaxel-induced neuropathies.
References
1.Hsu, L.-H., Chu, N.-M., Lin, Y.-F., and Kao, S.-H. (2019). G-Protein Coupled Estrogen Receptor in Breast Cancer. Int. J. Mol. Sci. 20, 306. 10.3390/ijms20020306.
2.Mallet C, Boudieu L, Lamoine S, Coudert C, Jacquot Y and Eschalier A (2021) The Antitumor Peptide ER?17p Exerts Anti-Hyperalgesic and Anti-Inflammatory Actions Through GPER in Mice. Front. Endocrinol. 12:578250. 10.3389/fendo.2021.578250
3.Jouffre, B., Acramel, A., Jacquot, Y., Daulhac, L., and Mallet, C. (2023). GPER involvement in inflammatory pain. Steroids 200, 109311. 10.1016/j.steroids.2023.109311.
3.Lappano, R., Mallet, C., Rizzuti, B., Grande, F., Galli, G., Byrne, C., Broutin, I., Boudieu, L., Eschalier, A., Jacquot, Y., et al. (2019). The Peptide ER?17p Is a GPER Inverse Agonist that Exerts Antiproliferative Effects in Breast Cancer Cells. Cells 8, 590. 10.3390/cells8060590.
4.Jouffre, B., Acramel, A., Belnou, M., Santolla, M.F., Talia, M., Lappano, R., Nemati, F., Decaudin, D., Khemtemourian, L., Liu, W.-Q., et al. (2023). Identification of a human estrogen receptor ? tetrapeptidic fragment with dual antiproliferative and anti-nociceptive action. Sci. Rep. 13, 1326. 10.1038/s41598-023-28062-9.
Presenting Author
Baptiste Jouffre
Poster Authors
Baptiste Jouffre
MSc
NeuroDol Université Clermont Auvergne
Lead Author
Alexandre Acramel
PharmD
CiTCoM, CNRS - UMR 8038, INSERM U1268, Faculty of Pharmacy of Paris, University Paris Cité
Lead Author
Pauline Gousseau
Neuro-Dol, Université Clermont Auvergne
Lead Author
Laurence Daulhac-Terrail
PharmD PhD
Neuro-Dol, Inserm U1107, Université Clermont Auvergne (France)
Lead Author
Yves Jacquot
PharmD PhD
CiTCoM, CNRS - UMR 8038, INSERM U1268, Faculty of Pharmacy of Paris, University Paris Cité
Lead Author
Christophe Mallet
PhD
Neuro-Dol, Inserm U1107, Université Clermont Auvergne (France)
Lead Author
Topics
- Specific Pain Conditions/Pain in Specific Populations: Cancer Pain & Palliative Care