The Role of Nerve Growth Factor in Neuropathic Pain Inhibition Produced by Resiniferatoxin Treatment in the Dorsal Root Ganglia

BACKGROUND: Resiniferatoxin (RTX), an excitotoxic agonist for vanilloid receptor 1, is a promising candidate for intractable pain treatment. OBJECTIVE: We evaluated the effects of RTX, applied to dorsal root ganglia (DRG) at high doses (1200 ng), in sensory-motor function and nerve growth factor (NGF) alterations in a photochemical sciatic nerve injury rat model. METHODS: Following RTX injection into the L3-6 DRG at high doses and behavioral evaluation, the rats were sacrificed and the DRG were tested by immunohistochemistry and mRNA analysis for NGF and its' receptors, tyrosine kinase A (TrkA) and p75. The correlation between neuropathic pain and NGF, TrkA, and p75 expression was analyzed. RESULTS: The treated rats had preserved touch, cold, pain, and high-heat sensations, and exhibited hypoalgesia to low-heat stimulation. After RTX treatment, TrkA and p75 altered their expressions from one neuronal type to another in the DRG. NGF and p75 expression changed from the small-size neurons in neuropathic rat DRG to the large- and medium-size neurons in non-neuropathic and RTX-treated animals, concomitantly with neuropathic pain suppression. TrkA was expressed in the small-size neurons in neuropathic rat DRG, and was drastically reduced in all size neurons after RTX treatment. NGF, TrkA, and p75 mRNA expression supported these phenotypic changes in the DRG. CONCLUSION: The pathway of NGF—TrkA expressed in the small-size neurons, associated with neuropathic pain, was shifted to the NGF—p75 pathway expressed in the large-size neurons after RTX treatment, in association with neuropathic pain inhibition. These findings may play an important role in clinical trial designs. ABBREVIATIONS: DRG, dorsal root ganglia IHC, immunohistochemistry mRNA, messenger ribonucleic acid NGF, nerve growth factor NP, neuropathic pain RTX, resiniferatoxin TrkA, tyrosine-kynase A VR1, vanilloid receptor 1