Gabapentin and its salicylaldehyde derivative alleviate allodynia and hypoalgesia in a cisplatin-induced neuropathic pain model

Cisplatin is an effective chemotherapeutic agent indicated in cancer chemotherapy. However, its clinical use is associated with peripheral neuropathy that invariably impairs patient quality of life. Gabapentin (GBP) is an effective analgesic for neuropathic pain conditions but its clinical efficacy in cisplatin-induced neuropathic pain (CINP) is limited, in addition to generating unwanted side-effects. In this study, a gabapentin-salicylaldehyde derivative [gabapentsal (GPS)] was synthesized and evaluated to explore any potential benefit in comparison with GBP in a rat model of CIPN. Administration of cisplatin (3.0 mg/kg/week, i.p.) for five consecutive weeks generated reproducible mechanical-allodynia (decreased paw withdrawal threshold to von Frey filament application; PWT, g) and thermal hypoalgesia (increased nociceptive reaction latency in the hot plate paradigm; s). Treatment with GBP or its derivative on the 37th day of the experimental protocol, dose dependently attenuated cisplatin-induced nocifensive behaviors. Accordingly, doses of GBP (50-100 mg/kg, i.p.) and GPS (25-100 mg/kg, i.p.) suppressed the expression of CINP by normalizing the PWT and hot plate response latency 1 h and 3 h post administration. In the rotarod paradigm, GBP at all doses markedly impaired motor performance, whilst GPS was devoid of motor incoordination except at the highest dose, when a mild impairment occurred. Salicylaldehyde alone had no effect on CINP or rotarod performance and neither was there any synergism when coadministered with GBP. These findings suggest that both GBP and GPS have beneficial effects in the neuropathic pain model though GPS may be potentially more useful in the management of CINP.