Variable sensitivity to noxious heat is mediated by differential expression of the CGRP gene.
Heat sensitivity shows considerable functional variability in humans and laboratory animals, and is fundamental to inflammatory and possibly neuropathic pain. In the mouse, at least, much of this variability is genetic because inbred strains differ robustly in their behavioral sensitivity to noxious heat. These strain differences are shown here to reflect differential responsiveness of primary afferent thermal nociceptors to heat stimuli. We further present convergent behavioral and electrophysiological evidence that the variable responses to noxious heat are due to strain-dependence of CGRP expression and sensitivity. Strain differences in behavioral response to noxious heat could be abolished by peripheral injection of CGRP, blockade of cutaneous and spinal CGRP receptors, or long-term inactivation of CGRP with a CGRP-binding Spiegelmer. Linkage mapping supports the contention that the genetic variant determining variable heat pain sensitivity across mouse strains affects the expression of the Calca gene that codes for CGRPalpha.
Mogil
Jeffrey S
JS
Department of Psychology and Centre for Research on Pain, McGill University, Montreal, QC, Canada H3A 1B1.
Miermeister
Frank
F
Seifert
Frank
F
Strasburg
Kate
K
Zimmermann
Katharina
K
Reinold
Heiko
H
Austin
Jean-Sebastien
JS
Bernardini
Nadia
N
Chesler
Elissa J
EJ
Hofmann
Heiko A
HA
Hordo
Christian
C
Messlinger
Karl
K
Nemmani
Kumar V S
KV
Rankin
Andrew L
AL
Ritchie
Jennifer
J
Siegling
Angela
A
Smith
Shad B
SB
Sotocinal
Susana
S
Vater
Axel
A
Lehto
Sonya G
SG
Klussmann
Sven
S
Quirion
Remi
R
Michaelis
Martin
M
Devor
Marshall
M
Reeh
Peter W
PW
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics*; D004594:Electrophysiology; D005260:Female; D005786:Gene Expression Regulation; D006358:Hot Temperature / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009619:Nociceptors / Q000378:metabolism; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology*; D013045:Species Specificity
D015740:Calcitonin Gene-Related Peptide