Adult dorsal root ganglion (DRG) cells are capable of neurite outgrowth in vitro as well as in vivo. We have investigated the influence of adenosine and analogs on the potential of cultured adult mouse DRG neurons to produce neurites in the presence and absence of nerve growth factor (NGF) which is a well-established trophic factor of sympathetic and sensory neurons during development. It is also believed to be essential for the maintenance or regulation of differentiated phenotypes of mature peripheral neurons. The results demonstrate that DRG neurons are modulated by purines in the absence of exogenous NGF. The addition of 100 microM adenosine to neurite-bearing DRG neurons inhibited neurite growth by 47% after 2-day exposures in vitro and by 50% after 5 days whereas in the presence of NGF this inhibition was reduced to 28% and 32%, respectively. 100 microM CHA (N(6)-cyclohexyl adenosine) alone reduced neurite total length by 47% after 2 days and by 48% after 5 days. 100 microM CGS21680 (2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamido adenosine hydrochloride) alone also reduced neurite total length by 46% after 2 days and by 58% after 5 days which was reduced to 21% and 37%, respectively, in the presence of 100 ng/ml NGF. The antagonist studies revealed that activation of A1 adenosine receptors is primarily responsible for the effect on neuritogenesis since the inclusion of 1 or 10 microM CPX (8-cyclopentyl-1,3-dipropyl xanthine) fully prevented the inhibitory activity of adenosine or CHA whereas DMPX (3,7-dimethyl-1-propargyl xanthine) did not prevent inhibition by CHA. The converse experiment yielded the consistent result that inhibition by the A2 receptor agonist CGS21680 could be prevented by CPX, but not DMPX.