Heat hyperalgesia and mechanical hypersensitivity induced by calcitonin gene-related peptide in a mouse model of neurofibromatosis

• Published in: PloS one Vol. 9; no. 9; p. e106767
• Main Authors: White, Stephanie, Marquez de Prado, Blanca, Russo, Andrew F, Hammond, Donna L
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03.09.2014; Public Library of Science (PLoS)
• Subjects: Allergy; Analgesics; Animals; Binding sites; Biology and Life Sciences; Biophysics; Calcitonin; Calcitonin gene-related peptide; Calcitonin Gene-Related Peptide - genetics; Calcitonin Gene-Related Peptide - metabolism; Cancer genetics; Capsaicin; Disease Models, Animal; Dorsal root ganglia; Experiments; Female; Formaldehyde; Ganglia; Gender differences; Genes; Genetic disorders; Genotypes; Guanosine triphosphatases; Heat; Hot Temperature; House mouse; Hyperalgesia; Hyperalgesia - genetics; Hyperalgesia - metabolism; Hyperalgesia - physiopathology; Hypersensitivity; Inflammation; Injection; Laboratory animals; Male; Mechanical stimuli; Medicine and Health Sciences; Mice; Migraine; Mutation; Neurofibromatoses - genetics; Neurofibromatoses - metabolism; Neurofibromatoses - physiopathology; Neurofibromatosis; Neurofibromin 1; Neurofibromin 1 - genetics; Neurofibromin 1 - metabolism; Neurological disorders; Pain; Pain perception; Peptides; Physiology; Proteins; Rodents; Sensitivity enhancement; Spinal cord; Studies; Touch; Tumors; United States > US; Iowa; Iowa City Iowa
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0106767

This study examined whether mice with a deficiency of neurofibromin, a Ras GTPase activating protein, exhibit a nociceptive phenotype and probed a possible contribution by calcitonin gene-related peptide. In the absence of inflammation, Nf1+/- mice (B6.129S6 Nf1/J) and wild type littermates responded comparably to heat or mechanical stimuli, except for a subtle enhanced mechanical sensitivity in female Nf1+/- mice. Nociceptive phenotype was also examined after inflammation induced by capsaicin and formalin, which release endogenous calcitonin gene-related peptide. Intraplantar injection of capsaicin evoked comparable heat hyperalgesia and mechanical hypersensitivity in Nf1+/- and wild type mice of both genders. Formalin injection caused a similar duration of licking in male Nf1+/- and wild type mice. Female Nf1+/- mice licked less than wild type mice, but displayed other nociceptive behaviors. In contrast, intraplantar injection of CGRP caused greater heat hyperalgesia in Nf1+/- mice of both genders compared to wild type mice. Male Nf1+/- mice also exhibited greater mechanical hypersensitivity; however, female Nf1+/- mice exhibited less mechanical hypersensitivity than their wild type littermates. Transcripts for calcitonin gene-related peptide were similar in the dorsal root ganglia of both genotypes and genders. Transcripts for receptor activity-modifying protein-1, which is rate-limiting for the calcitonin gene-related peptide receptor, in the spinal cord were comparable for both genotypes and genders. The increased responsiveness to intraplantar calcitonin gene-related peptide suggests that the peripheral actions of calcitonin gene-related peptide are enhanced as a result of the neurofibromin deficit. The analgesic efficacy of calcitonin gene-related peptide receptor antagonists may therefore merit investigation in neurofibromatosis patients.