Chronic constriction injury of the sciatic nerve is an animal model for neuropathic pain. In this model, the analgesic potency of systemic morphine was significantly diminished in nerve-injured mice (ED(50) 19.4 mg/kg) compared with sham-operated mice (ED(50) 3.3 mg/kg) using a unilateral hot plate withdrawal test, with a similar reduction in sensitivity of intrathecal morphine. The sciatic nerve injury resulted in a reorganization of the dorsal root ganglion (DRG) neurons. Immunohistochemically, the chronic constriction injury triggered a withdrawal of C-fibers from the ipsilateral dorsal horn of the spinal cord. Although A-beta terminals centrally sprouted into Lamina II of the dorsal horn of the spinal cord, the peripheral A-beta fibers in the skin retracted from the epidermis to deeper layers of the dermis. To explore the functional significance of these dermal changes, we examined the topical morphine and lidocaine analgesia following chronic sciatic nerve constriction. Both morphine and lidocaine retained topical activity following chronic sciatic nerve injury, but their analgesic dose-response curves were shifted to the right when compared to sham-operated mice. Thus, the chronic nerve constriction injury model is associated with pathological changes in distribution of the central and peripheral axons of the dorsal root ganglion neurons that correspond to a decreased pharmacological sensitivity to topical analgesic agents.