title: Heat hyperalgesia and mechanical hypersensitivity induced by calcitonin gene-related peptide in a mouse model of neurofibromatosis.
abstract: 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<tm1Fcr>/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.
authors.affiliation: Department of Anesthesia, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: White
authors.affiliation: Department of Anesthesia, University of Iowa, Iowa City, Iowa, United States of America; Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Blanca
authors.initials: B
authors.lastname: Marquez de Prado
authors.affiliation: Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Russo
authors.affiliation: Department of Anesthesia, University of Iowa, Iowa City, Iowa, United States of America; Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Hammond
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006358:Hot Temperature; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D017253:Neurofibromatoses / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism; D014110:Touch
chemical_list: D025542:Neurofibromin 1; D015740:Calcitonin Gene-Related Peptide