This study was designed to investigate the effects of multiple denervation procedures on calcitonin gene-related peptide- and substance P-immunoreactive neurons in sympathetic and sensory cranial ganglia and in selected targets. Sympathectomy by long-term guanethidine treatment induced a pronounced increase in calcitonin gene-related peptide-immunoreactive and substance P-immunoreactive nerve fibres in all the tissues investigated, in contrast to a significant reduction of immunoreactive cell bodies. Neonatal capsaicin treatment abolished substance P immunoreactivity in many targets and caused a dramatic reduction of substance P-immunoreactive sensory nerve cell bodies; calcitonin gene-related peptide-immunoreactive nerve density was decreased, but the number of immunoreactive nerve cell bodies was unchanged. Guanethidine treatment of capsaicin-injected rats reversed the loss of calcitonin gene-related peptide-immunoreactive nerves, but not that of substance P-immunoreactive neurons. In the iris, capsaicin treatment had little effect on calcitonin gene-related peptide- and substance P-immunoreactive nerves, suggesting that in rats the majority of these fibres originate from capsaicin-insensitive neurons. The results suggest that the denervation procedures used in this study alter the synthesis and transport of neuropeptides in sensory neurons in conjunction with changes in the number of nerve fibres.