title: Methotrexate chemotherapy triggers touch-evoked pain and increased CGRP-positive sensory fibres in the tibial periosteum of young rats.
abstract: 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.
authors.affiliation: Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001, Australia.
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Zhou
authors.affiliation: Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001, Australia.
authors.forename: Yingnan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001, Australia.
authors.forename: Xin-Fu
authors.initials: XF
authors.lastname: Zhou
authors.affiliation: Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001, Australia. Electronic address: Cory.Xian@unisa.edu.au.
authors.forename: Cory J
authors.initials: CJ
authors.lastname: Xian
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D008297:Male; D008727:Methotrexate / Q000009:adverse effects*; D010146:Pain / Q000139:chemically induced*; D010521:Periosteum / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013977:Tibia / Q000187:drug effects* / Q000378:metabolism; D014110:Touch
chemical_list: D000964:Antimetabolites, Antineoplastic; D015740:Calcitonin Gene-Related Peptide; D008727:Methotrexate
keywords: Bone innervation; Bone pain; Cancer chemotherapy; MTX; Mechanical allodynia; Methotrexate