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Short-term diabetes causes sensory disorders in rats ranging from thermal hypoalgesia to exaggerated behavioral responses to other sensory stimuli. As impaired neurotrophic support may promote sensory nerve disorders during diabetes, the authors investigated whether TX14(A), a neurotrophic peptide derived from prosaposin, was able to ameliorate nerve disorders in diabetic rats.TX14(A) was delivered by intraperitoneal or intrathecal injection to control or streptozotocin-diabetic rats in either single or multiple (three times weekly) dose regimens. Efficacy was measured against diabetes-induced disorders of sensory nerve conduction velocity, paw withdrawal latency to radiant heat, tactile response thresholds to von Frey filaments, and flinching after paw formalin injection.Prolonged TX14(A) treatment of diabetic rats prevented the progressive decline in large sensory fiber conduction velocity in the sciatic nerve, development of paw thermal hypoalgesia, and increased flinching after paw formalin injection. The effect on formalin hyperalgesia persisted for 48 h but not 72 h after injection. No effects were noted in control rats. A single injection of TX14(A) 30 min before testing did not alter thermal response latencies in control or diabetic rats but prevented formalin hyperalgesia in diabetic rats. Tactile allodynia and the prolonged paw thermal hyperalgesia to radiant heat after intrathecal delivery of substance P were also dose-dependently ameliorated in diabetic rats by a single injection of TX14(A), whereas no effects were observed on the responses to these tests in control rats.TX14(A) exhibits both neuroprotective and acute antihyperalgesic properties in diabetic rats without altering normal nociceptive function.