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.
Highlights
Neurofibromatosis 1 (NF1) is an autosomal dominant disorder that results in reduced levels of neurofibromin, a GTPase activating protein (GAP) involved in the regulation of Ras signaling
High densities of calcitonin gene-related peptide (CGRP)-immunoreactive fibers are present in neurofibromas in patients [13]
The results of this study do not support the hypothesis that a reduction in neurofibromin is associated with enhanced acute or inflammatory nociception, and confirm the conclusions of another recent comprehensive analysis of male Nf1+/2 mice
Summary
Neurofibromatosis 1 (NF1) is an autosomal dominant disorder that results in reduced levels of neurofibromin, a GTPase activating protein (GAP) involved in the regulation of Ras signaling (i.e. a Ras-GAP). This genetic disorder affects one in 3500 births worldwide – an incidence that equates to ,90,000 Americans and a million persons worldwide [1,2,3,4]. The chronic nature of the pain, as well as its lancinating and paroxysmal character, contribute to the poor quality of life for patients with NF [8]. There is a great need for mechanistic based pharmacotherapies for the relief of pain in this patient population
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