Assessment of Pain and Itch Behavior in a Mouse Model of Neurofibromatosis Type 1

Abstract

Neurofibromatosis type 1 (NF1) is characterized primarily by tumor formation in the nervous system, but patients report other neurological complications including pain and itch. Individuals with NF1 harbor 1 mutated NF1 allele causing heterozygous expression in all of their cells. In mice, Nf1 heterozygosity leads to hyperexcitability of sensory neurons and hyperproliferation of mast cells, both of which could lead to increased hypersensitivity and scratching in response to noxious and pruritic stimuli. To determine whether Nf1 heterozygosity may increase pain and itch behaviors independent of secondary effects of tumor formation, we used mice with a targeted, heterozygous Nf1 gene deletion (Nf1±) that lack tumors. Nf1± mice exhibited normal baseline responses to thermal and mechanical stimuli. Moreover, similar to wild-type littermates, Nf1± mice developed inflammation-induced heat and mechanical hypersensitivity, capsaicin-induced nocifensive behavior, histamine-dependent or -independent scratching, and chronic constriction injury-induced cold allodynia. However, Nf1± mice exhibited an attenuated first phase of formalin-induced spontaneous behavior and expedited resolution of formalin-induced heat hypersensitivity. These results are not consistent with the hypothesis that Nf1 heterozygosity alone is sufficient to increase pain and itch sensation in mice, and they suggest that additional mechanisms may underlie reports of increased pain and itch in NF1 patients. PerspectiveThis study assessed whether Nf1 heterozygosity in mice increased hypersensitivity and scratching following noxious and pruritic stimuli. Using Nf1± mice lacking tumors, this study finds no increases in pain or itch behavior, suggesting that there is no predisposition for either clinical symptom solely due to Nf1 heterozygosity.