Original Full Length ArticleMethotrexate chemotherapy triggers touch-evoked pain and increased CGRP-positive sensory fibres in the tibial periosteum of young rats

- Bone pain caused by cancer chemotherapy is well-recognized, but underlying mechanisms are poorly understood.
- Effects of anti-metabolite methotrexate on leg pain and bone sensory innervation were examined over a time course in rats.
- MTX treatment increased mechanical allodynia in hind limbs which led to reduced mobility during the recovery phase.
- MTX treatment altered CGRP + ve sensory nerve innervation in tibial periosteum during bone damage and repair phases.
- This experimental model may provide an excellent tool to study chemotherapy-induced bone pain and immobility and their underlying mechanisms.

Although bone pain caused by cancer chemotherapy is a well-recognized and significant problem, with approximately 1 in 10 childhood cancer patients being reported to experience isolated bone pain along with other skeletal complications, the underlying mechanisms are poorly understood and there is no specific treatment. In this study, effects of methotrexate (MTX) treatment on pain in the hind legs and the extent of sensory innervation of the tibial bone were examined through a 20-day time course in young rats after 5 daily 0.75 mg/kg MTX injections. MTX treatment increased von-Frey filament stimulation-induced mechanical allodynia and palpation nocifensive score in the tibia. MTX-treated rats showed trends in reduced loading (numbers of stands) on hind limbs after palpation, commencing early during treatment and 2 weeks after the end of treatment despite no signs of ongoing pain during normal locomotion. Immunohistochemical analyses showed an increase in innervation of calcitonin gene-related peptide (CGRP)-positive sensory nerve fibres in tibial periosteum on days preceding and overlapping with those rats with touch-evoked pain responses and the bone repair phase. These data suggest that methotrexate chemotherapy triggers touch-evoked pain involving enhanced sensory nerve innervation of the bone.