Peripheral benzodiazepine receptors (PBR) and their endogenous ligands, the diazepam-binding inhibitor derived-peptides, are present in Schwann cells in the peripheral nervous system. The aim of this study was to determine the influence of reversible (freeze-injury) and permanent (transection and ligature) nerve lesion on PBR density and on the levels of their endogenous ligands, by autoradiography (using [3H]PK11195) and radioimmunoassay (using antisera directed against the octadecaneuropeptide (ODN), a diazepam-binding inhibitor fragment). The potential role of PBR on peripheral nerve steroidogenesis, was studied by investigating the effect of specific PBR agonists and antagonists on pregnenolone levels in the sciatic nerve. Sixteen to 30 days after nerve lesion, PBR density and ODN-LI level were highly increased. Their expression returned to normal level when regeneration was completed 60 days after freeze-injury, but remained elevated when regeneration did not occur in transected distal stumps. Reverse-phase HPLC analysis of ODN-LI showed that in control nerve extracts, the major immunoreactive peak co-elutes with triakontatetraneuropeptide (TTN). After freeze-injury, intermediate molecular forms eluting between ODN and TTN were predominant and remained elevated at day 60. The greater accumulation of intermediate forms when regeneration is allowed to occur may indicate a particular role of these forms in axonal elongation and myelination. Ro5-4864, a high affinity PBR agonist increased pregnenolone concentration in the sciatic nerve. This effect was antagonised by PK11195, a high affinity PBR antagonist, which had no effect on pregnenolone basal level, indicating a specific action of PBR in neurosteroid production. These results suggest a role for PBR and their endogenous ligands in peripheral nerve regeneration. A trophic effect could be exerted via stimulation of steroid synthesis.