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␣.calcitonin gene-related peptide ͉ genetic ͉ Calca ͉ nociceptors ͉ pain H umans display wide individual variability in sensitivity to pain.Although the relative importance of genes versus experience in human pain perception is unclear, recent studies have shown that mouse strains display large differences in behavioral pain sensitivity that are heritable (1). These same studies revealed genetic correlations between baseline thermal nociception and the hypersensitivity states associated with inflammatory and neuropathic pain (2). Of the strains examined, AKR and C57BL͞6 mice displayed the largest and most consistent differences in several different assays of thermal nociception, with AKR being much less sensitive than C57BL͞6. In contrast, AKR mice exhibit more robust heat hyperalgesia after inflammatory or nerve injury (1). Despite our considerable knowledge of the behavioral ''phenomics'' of baseline heat pain and hyperalgesia, there are almost no published data regarding the underlying cellular or molecular mechanisms. Here we show that the observed strain differences in response to thermal stimulation are caused by corresponding differences in the functioning of primary afferent nociceptors. The differences in nociceptor sensitivity, in turn, are caused by the presence of and sensitivity to the neuropeptide calcitonin gene-related polypeptide (CGRP). Finally, linkage mapping revealed a candidate gene likely responsible for the strain difference: Calca, the gene encoding CGRP␣.CGRP␣ is a secretory neuropeptide released from thin nerve fibers at their peripheral and central terminals, which is thought to contribute importantly to neurogenic inflammation in the skin and to central sensitization in the spinal cord (3-6). CGRP acts through a G s protein-coupled receptor complex to activate cAMPdependent protein kinase (PKA). PKA, via the transcription factor cAMP response element-binding protein, enhances expression of pronociceptive genes including the Calca gene itself (7-9). Moreover, many...

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