Effect of Experimental Gestational Diabetes Mellitus on Mechanical Sensitivity, Capsaicin-Induced Pain Behaviors and Hind Paw Glabrous Skin Innervation of Male and Female Mouse Offspring

Abstract

Enriqueta Munoz-Islas,1 Cecilia Esther Elizondo-Martinez,1 Mariela Gutierrez-Lopez,1 Rosa Issel Acosta-Gonzalez,1 Veronica Zaga-Clavellina,2 Addy Cecilia Helguera-Repetto,3 Martha Beatriz Ramirez-Rosas,1 E Alfonso Romero-Sandoval,4 Juan Miguel Jimenez-Andrade1 1Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa, Tamaulipas, Mexico; 2Departamento de Fisiología y Desarrollo Celular, Instituto Nacional de Perinatología, Ciudad de México, Mexico; 3Departamento de Inmunobioquímica, Instituto Nacional de Perinatología, Ciudad de México, Mexico; 4Department of Anesthesiology, Wake Forest University School of Medicine, Winston Salem, NC, USACorrespondence: Enriqueta Munoz-Islas Calle 16 y Lago de Chapala, Col. Aztlán C.P.88740, Reynosa, Tamaulipas, MexicoTel [phone]Fax [phone]Email [email protected]: Gestational diabetes mellitus (GDM) induces cardiovascular and metabolic disturbances in offspring. However, the effects of GDM in pain processing in offspring and whether male and female offspring are equally affected is not well known. Thus, we determined: i) whether GDM in mice affects offspring hindpaw mechanical sensitivity, capsaicin-induced spontaneous pain-like behaviors, and epidermal nerve fiber density (ENFD); and ii) whether there is sexual dimorphism in these parameters in offspring from GDM dams.Methods: GDM was induced in pregnant ICR mice via i.p. streptozotocin (STZ). Then, glucose levels from dams and offspring were determined. Male and female offspring 2– 3 months of age were evaluated for: a) baseline mechanical sensitivity of the hind paw by using von Frey filaments; b) number of flinches and time spent guarding induced by intraplantar capsaicin (0.1%); and c) density of PGP-9.5 and CGRP axons in the epidermis from the hind paw glabrous skin.Results: Prepartum levels of glucose in STZ-treated dams were significantly increased compared to vehicle-treated dams; however, GDM or vehicle offspring displayed normal and similar blood glucose levels. Male and female GDM offspring showed significantly greater mechanical sensitivity and capsaicin-induced pain behaviors compared to vehicle offspring. Male GDM offspring displayed a slightly more intense nociceptive phenotype in the capsaicin test. PGP-9.5 and CGRP ENFD in hind paw glabrous skin were greater in male and female GDM offspring versus their controls. Sexual dimorphism was generally not observed in GDM offspring in most of the studied parameters.Conclusion: These results suggest GDM induced greater pain-like behaviors in adult offspring regardless of sex along with an increased ENFD of PGP-9.5 and CGRP in the hind paw glabrous skin. We show that GDM peripheral neuropathy differs from diabetic peripheral neuropathy acquired in adulthood and set the foundation to further study this in human babies exposed to GDM.Keywords: offspring, long-term effects, nociception, CGRP

Keywords

• offspring
• long-term effects
• nociception
• cgrp.