We tested the hypothesis that the 5HT1DR, the primary antinociceptive target of triptans, is differentially distributed in tissues responsible for migraine pain. The density of 5HT1DR was quantified in tissues obtained from adult female rats with Western blot analysis. Receptor location was assessed with immunohistochemistry. The density of 5HT1DR was significantly greater in tissues known to produce migraine-like pain (i.e. circle of Willis and dura) than in structures in which triptans have no antinociceptive efficacy (i.e. temporalis muscle). 5HT1DR-like immunoreactivity was restricted to neuronal fibres, where it colocalized with calcitonin gene-related peptide and tyrosine hydroxylase immunoreactive fibres. These results are consistent with our hypothesis that the limited therapeutic profile of triptans could reflect its differential peripheral distribution and that the antinociceptive efficacy reflects inhibition of neuropeptide release from sensory afferents. An additional site of action at sympathetic efferents is also suggested.