Many painful conditions occur more frequently in women, and estrogen is a predisposing factor. Estrogen may contribute to some pain syndromes by enhancing axon outgrowth by sensory dorsal root ganglion (DRG) neurons. The objective of the present study was to define mechanisms by which estrogen elicits axon sprouting. The estrogen receptor- agonist propyl pyrazole triol induced neurite outgrowth from cultured neonatal DRG neurons whereas the estrogen receptor- agonist diarylpropionitrile was ineffective. 17-estradiol (E2) elicited sprouting from peripherin-positive unmyelinated neurons but not larger NF200-positive myelinated neurons. Microarray analysis showed that E2 upregulates angiotensin II receptor type 2 (AT2) mRNA in vitro, and studies in adult rats confirmed increased DRG mRNA and protein in vivo. AT2 plays a central role in E2-induced axon sprouting, as AT2 blockade by PD123319 eliminated estrogen-mediated sprouting in vitro. We assessed whether AT2 may be responding to locally synthesized angiotensin II. DRG from adult rats expressed mRNA for renin, angiotensinogen, and angiotensin converting enzyme (ACE), and protein products were present and occasionally colocalized within neurons and other DRG cells. We determined if locally synthesized angiotensin II plays a role in estrogen-mediated sprouting by blocking its formation using the ACE inhibitor enalapril. ACE inhibition prevented estrogen-induced neuritogenesis. These findings support the hypothesis that estrogen promotes DRG nociceptor axon sprouting by upregulating the AT2 receptor, and that locally synthesized angiotensin II can induce axon formation. Estrogen may therefore contribute to some pain syndromes by enhancing the pro-neuritogenic effects of AT2 activation by angiotensin II.