To evaluate the possible role of neuropeptide immunoreactive primary sensory neurons on the development of nociceptive dysfunction in diabetes, the absolute numbers of immunoreactive substance P and calcitonin gene-related peptide (CGRP) dorsal root ganglion (DRG) cell bodies were estimated in diabetic and nondiabetic BALB/C (p75(+/+)) and p75 receptor knockout (p75(-/-)) mice with unilateral sciatic nerve crush. The total numbers of immunoreactive substance P A-cells, substance P B-cells, CGRP A-cells, and CGRP B-cells in L5DRG were estimated using semithick consecutive sections and the optical fractionator. After 4 weeks of streptozotocin-induced diabetes, the number of immunoreactive CGRP A-cells was reduced from 692 +/- 122 to 489 +/- 125 (P = 0.004) in p75(+/+) mice on the noncrushed side. In p75(-/-) mice, there was no such effect of diabetes on the immunoreactive CGRP A-cell number. In p75(+/+) and p75(-/-) mice, there was no effect of diabetes on the immunoreactive CGRP B-cell number, nor was there any effect of diabetes on the immunoreactive substance P B-cell number. Sciatic nerve crush was associated with a substantial loss of L5DRG B-cells in diabetic and nondiabetic p75(+/+) mice and with substantial loss of immunoreactive substance P cells in diabetic p75(+/+) mice. In diabetic and nondiabetic p75(-/-) mice, there was no crush effect on neuropeptide expression. It is concluded that experimental diabetes in the mouse is associated with loss of immunoreactive CGRP primary sensory neurons of the A-cell phenotype, that this loss could play a role for the touch-evoked nociception in the model, and that the neuronal immunoreactive CGRP abnormality possibly is mediated by activation of the p75 neurotrophin receptor.