Chronic pain caused by nerve injury and inflammation is more common in the elderly. However, mechanisms underlying this phenomenon are unclear. Higher sensitivity of sensory neurons to free radicals has been suggested as one possibility. The production of free radicals can be induced by various agents, including the highly toxic protein β-amyloid (Aβ), which is found in higher amounts in the brains of Alzheimer's Disease patients. In dorsal root ganglion (DRG) cultures exposed to Aβ, we examined cellular toxicity and peptide expression, in particular calcitonin gene-related peptide (CGRP), a peptide which is abundantly expressed by nociceptive afferents and is known to be involved in pain processes. Exposure of cultured rat DRG neurons to Aβ25−35 or Aβ1−40 (10 or 20 µm for 24–96 h) increased trypan blue-stained cells in a concentration- and time-dependent manner, thus, indicating cellular toxicity. These treatments also increased the number of CGRP immunoreactive (IR) neurons while decreasing the number of neuropeptide Y- and galanin-IR neurons. The free radical scavenger, superoxide dismutase, attenuated both the toxicity and neuropeptide changes induced by Aβ, thus, suggesting that oxidative stress probably contributes to these effects. Exposure of cultured DRG neurons to Aβ also increased the number of protein kinase Cα (PKCα)-IR neurons. The PKC inhibitors, chelerythrine chloride and Gö6976, significantly augmented Aβ-induced cellular toxicity while attenuating the increases in CGRP-and PKCα-IR cells, supporting the notion of a protective role for PKC in Aβ insults. These in vitro data suggest that Aβ peptides may, in addition to causing neurotoxicity, regulate neuropeptide expression in primary afferents. This finding could be relevant to the higher incidence of neuropathic pain that occurs with ageing.