Pituitary adenylate cyclase-activating polypeptide (PACAP) has recently been demonstrated in sensory neurons. In the present study on rat 17.5% of all neurons, mainly of small size, contained PACAP in normal dorsal root ganglia (DRGs). Transection of the sciatic nerve induced a rapid and strong upregulation in PACAP peptide and mRNA levels which could be seen already after 15 h. After 3 days more than 51.5% of neurons of different sizes expressed PACAP. However, the intensity of PACAP-LI in the DRG neurons declined after 10 days. Thirty days after axotomy, 56.7% of the DRG neurons still expressed PACAP, but with a low intensity, in fact even lower than in normal controls. No VIP- or NPY-positive neurons were observed in normal or axotomized DRGs at 15 h. However a distinct increase in VIP and NPY levels were seen 3 days after the lesion, and their levels were considerably higher after 30 days. PACAP was often present in neurons expressing VIP, NPY and/or galanin. Thus, 3 days after injury, PACAP was present in 84.4%, 95.7%, and 76.8% of the VIP-, NPY-, and galanin-positive neurons, respectively. PACAP was also found in nerve fibers in control sciatic nerves. After nerve ligation, accumulation of PACAP was seen mainly proximal to the injury but also distally, suggesting both anterograde and retrograde transport of the peptide. Also a moderate increase (about 20%) in PACAP levels was found in the superficial spinal dorsal horn 3 days after nerve transection. Taken together, our results suggest that PACAP is involved in the response to nerve injury. The very high levels of expression in different populations of DRG neurons after axotomy, and its different time course as compared to galanin, NPY and VIP indicate that it may play a complementary and/or different role than these peptides in the adaptation to nerve injury, especially in its early phase.