Bortezomib (BTZ) is an essential part for multiple myeloma treatment. It is highly effective, but serious side effects like painful polyneuropathy limit its application. In some patients, painfulness resolves after discontinuation of the therapy but in others it persists. One of the possible recovery mechanism is the resealing of the blood nerve barrier (BNB) shielding the vulnerable peripheral nerve from toxic substances. Using a preclinical model of bortezomib-induced polyneuropathy (BIPN) and a cohort of patients with BIPN we analyzed the transcriptomic signature and networks of the affected peripheral nerve. We identified the CNS barrier protein claudin-11 (Cldn11) as a marker for pain hypersensitivity and subsequent resolution. Furthermore, circadian genes were restored, the immune system was deactivated, and peri- and epineurial genes emerged. Functionally, the perineurial barrier was resealed for small molecules and small axons were less swollen. Netrin-1 as a barrier sealer was also upregulated during recovery on in nerve and skin in rodents. Patients with painful BIPN had higher Ntn1 in the skin when the somatosensory system remained intact. In summary, recovery in BIPN a characterized by a re-expression of barrier proteins like Cldn11, normalization of clock genes, upregulation of protective growth factors, remodeling of the extracellular matrix, and anti-inflammatory mechanisms in rodents and man.