A nitric oxide (NO)-donating gabapentin, NCX 1236, exerts marked anti-allodynic/anti-hyperalgesic effects in rodent models of neuropathic pain

Abstract

Nitric oxide (NO) plays a role in the development and maintenance of pain following nerve injury. This study was conducted to address the anti-allodynic/anti-hyperalgesic effects of NCX 1236, a novel NO-donating gabapentin, using three well defined rodent models, namely: the formalin-induced hyperalgesia in mice, the chronic constriction injury (CCI) in mice and the spinal nerve ligation (SNL) in rats. Plasma gabapentin exposure after treatment with NCX 1236 and gabapentin was also monitored. NCX 1236 resulted in similar gabapentin plasma exposure as for gabapentin when administered orally at equimolar doses. More specifically, gabapentin plasma levels increased rapidly after oral administration of either gabapentin or NCX 1236 (Tmax=30 min) and decayed during the following hours to reach basal levels 6h post-dosing. Like gabapentin (30 mg/kg, po), equimolar doses of NCX 1236 did not significantly modify the 1st phase of formalin-induced hyperalgesia (199±20; 252±44, 188±32 sec, respectively for vehicle, gabapentin and NCX 1236). However, NCX 1236 diminished the licking/flinching time more efficiently than gabapentin during the 2nd phase of this test (417±46; 301±37*; 195±30 sec*#, respectively for vehicle, gabapentin and NCX 1236, *p<0.05 vs. vehicle, #p<0.05 vs. gabapentin). In the CCI mice model, a single oral administration of NCX 1236 inhibited thermal hyperalgesia more effectively than gabapentin at similar exposure level (thermal threshold: 4.6±0.3, 5.8±0.5* and 7.7±0.5 sec*# for vehicle, gabapentin and NCX 1236, *p<0.05 vs. vehicle, #p<0.05 vs. gabapentin). Finally, NCX 1236 demonstrated superior activity compared to gabapentin on mechanical allodynia in SNL rats (mechanical threshold: 4.4±1.8, 3.8±1.2 and 10.7±2.2g*#, respectively for vehicle, gabapentin and NCX 1236, *p<0.05 vs. vehicle, #p<0.05 vs. gabapentin). These data suggest that, by virtue of its NO-donating properties, NCX 1236 reduces thermal and mechanical hyperalgesia/allodynia more efficiently than gabapentin at similar exposure in well defined rodent models of neuropathic pain. Nitric oxide (NO) plays a role in the development and maintenance of pain following nerve injury. This study was conducted to address the anti-allodynic/anti-hyperalgesic effects of NCX 1236, a novel NO-donating gabapentin, using three well defined rodent models, namely: the formalin-induced hyperalgesia in mice, the chronic constriction injury (CCI) in mice and the spinal nerve ligation (SNL) in rats. Plasma gabapentin exposure after treatment with NCX 1236 and gabapentin was also monitored. NCX 1236 resulted in similar gabapentin plasma exposure as for gabapentin when administered orally at equimolar doses. More specifically, gabapentin plasma levels increased rapidly after oral administration of either gabapentin or NCX 1236 (Tmax=30 min) and decayed during the following hours to reach basal levels 6h post-dosing. Like gabapentin (30 mg/kg, po), equimolar doses of NCX 1236 did not significantly modify the 1st phase of formalin-induced hyperalgesia (199±20; 252±44, 188±32 sec, respectively for vehicle, gabapentin and NCX 1236). However, NCX 1236 diminished the licking/flinching time more efficiently than gabapentin during the 2nd phase of this test (417±46; 301±37*; 195±30 sec*#, respectively for vehicle, gabapentin and NCX 1236, *p<0.05 vs. vehicle, #p<0.05 vs. gabapentin). In the CCI mice model, a single oral administration of NCX 1236 inhibited thermal hyperalgesia more effectively than gabapentin at similar exposure level (thermal threshold: 4.6±0.3, 5.8±0.5* and 7.7±0.5 sec*# for vehicle, gabapentin and NCX 1236, *p<0.05 vs. vehicle, #p<0.05 vs. gabapentin). Finally, NCX 1236 demonstrated superior activity compared to gabapentin on mechanical allodynia in SNL rats (mechanical threshold: 4.4±1.8, 3.8±1.2 and 10.7±2.2g*#, respectively for vehicle, gabapentin and NCX 1236, *p<0.05 vs. vehicle, #p<0.05 vs. gabapentin). These data suggest that, by virtue of its NO-donating properties, NCX 1236 reduces thermal and mechanical hyperalgesia/allodynia more efficiently than gabapentin at similar exposure in well defined rodent models of neuropathic pain.