Evaluating cytidine, uridine, and gabapentin combinations for pain modulation and p-CREB expression in neuropathic model

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AIMS: To evaluate the analgesic and neuroprotective effects of cytidine, uridine, and gabapentin-administered alone and in combination-in models of diabetic neuropathy and formalin-induced acute and inflammatory pain. MATERIALS & METHODS: Oral doses of cytidine, uridine, and gabapentin (100 mg/kg each) were administered to rats with streptozotocin-induced diabetic neuropathy and in a formalin test model. Behavioral responses were recorded at 30, 60, and 120 minutes following treatment after five weeks of diabetes induction. Spinal cord p-CREB expression was measured to assess molecular changes, and pretreatments with naloxone, yohimbine, and methysergide were employed to explore opioid, adrenergic, and serotonergic contributions. RESULTS: All treatments significantly reduced formalin-induced pain in both acute and inflammatory phases (p < 0.05; p < 0.001) and increased mechanical pain thresholds in the diabetic neuropathy model at all-time points (p < 0.05). Combination therapy proved more effective than gabapentin alone (p < 0.05) and was associated with decreased spinal p-CREB levels, indicating altered anti-nociceptive signaling. CONCLUSIONS: The combined use of cytidine, uridine, and gabapentin enhances analgesia and neuroprotection compared to monotherapy, supporting its potential as a novel, analgesic-free treatment strategy for diabetic neuropathy.