Abstract
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 CGRP