Activity of nicorandil, a nicotinamide derivative with a nitrate group, in the experimental model of pain induced by formaldehyde in mice.

Nicorandil (2-nicotinamide ethyl nitrate), an antianginal drug characterized by the coupling of nicotinamide with a nitric oxide (NO) donor, activates guanylyl cyclase and opens ATP-dependent K(+) channels. In the present study, we investigated the effects induced by per os (p.o.) administration of nicorandil (12.5, 25 or 50 mg/kg) or equimolar doses (corresponding to the highest dose of nicorandil) of N-(2-hydroxyethyl) nicotinamide (NHN), its main metabolite, or nicotinamide in the model of nociceptive response induced by formaldehyde in mice. Nicorandil, but not NHN or nicotinamide, inhibited the second phase of the nociceptive response. This activity was observed when nicorandil was administered between 30 and 120 min before the injection of formaldehyde. Ipsilateral intraplantar injection of nicorandil (125, 250 or 500 µg/paw) did not inhibit the nociceptive response. After p.o. administration of nicorandil (50 mg/kg), peak plasma concentrations of this compound and NHN were observed 0.63 and 4 h later, respectively. Nicotinamide concentrations were not increased after administration of nicorandil. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1 or 2 mg/kg), a guanylyl cyclase inhibitor, partially attenuated the antinociceptive activity of nicorandil. However, this activity was not changed by glibenclamide (30 or 60 mg/kg), an inhibitor of ATP-dependent K(+) channels. In conclusion, we demonstrated the antinociceptive activity of nicorandil in a model of pain that exhibits both a nociceptive and an inflammatory profile. This activity is not mediated by nicotinamide or NHN. The coupling of an NO-donor to nicotinamide results in a compound with an increased potency. The NO-cGMP pathway, but not ATP-dependent K(+) channels, partially mediates the antinociceptive activity of nicorandil.

Antinociceptive and anti-inflammatory activities of nicotinamide and its isomers in different experimental models.

Although there is evidence for the anti-inflammatory activity of nicotinamide, there is no evaluation of its effects in models of nociceptive and inflammatory pain. In addition, there is no information about the potential anti-inflammatory and antinociceptive activities of the nicotinamide isomers, picolinamide and isonicotinamide. Per os (p.o.) administration of nicotinamide (1000 mg/kg, -1h) inhibited the first and second phases of the nociceptive response induced by formalin in mice. In the model of nociceptive pain, exposure of mice to a hot-plate (50°C), nicotinamide (1000 mg/kg, -1h) also presented antinociceptive activity. Nicotinamide (500 mg/kg, -1 and 3h) also inhibited the mechanical allodynia induced by carrageenan in rats, a model of inflammatory pain. In addition to inhibiting the nociceptive response, nicotinamide (500 or 1000 mg/kg, -1 and 3h) inhibited the paw edema induced by carrageenan in mice and rats. P.o. administration of picolinamide (125 mg/kg, -1h) and isonicotinamide (500 or 1000 mg/kg, -1h) inhibited the second phase of the nociceptive response induced by formalin in mice. The paw edema induced by carrageenan in mice was also inhibited by isonicotinamide (500 or 1000 mg/kg, -1h) and picolinamide (125 mg/kg, -1h and 3h). The results represent the first demonstration of the activity of nicotinamide and its isomers in models of nociceptive and inflammatory pain and provide support to their anti-inflammatory activity. The demonstration of new activities for nicotinamide is important as it may contribute to expand its use in the treatment of other pathological conditions.

Peripheral 5-HT1B and 5-HT2A receptors mediate the nociceptive response induced by 5-hydroxytryptamine in mice.

While the role of 5-hydroxytryptamine (5-HT, serotonin) in the nociceptive processing has been widely investigated in the central nervous system, information regarding its role in peripheral tissues is still lacking. Noteworthy, 5-HT induces phenotypic changes of nociceptors and peripheral injection induces pain in humans and nociceptive response in rodents. However, local receptors involved in 5-HT effects are not well characterized. Thus, we aimed to investigate the role of 5-HT and some of its receptors in the peripheral nociceptive processing in mice. Intraplantar injection of 5-HT (10, 20 or 40 µg) into the hind-paw of mice induced paw licking behavior, which was inhibited by previous intraplantar treatment with cyproheptadine (5-HT(1) and 5-HT(2) antagonist; 0.5 or 5 µg), mianserin (5-HT(2) and 5-HT(6) antagonist; 0.1 µg), isamoltane (5-HT(1B) antagonist; 0.5 or 5 µg) and ketanserin (5-HT(2A) antagonist; 0.1 or 1 µg), but not by BRL 15572 (5-HT(1D) antagonist; 1 or 10 µg), ondansetron (5-HT(3) antagonist; 1, 5, 10 or 20 µg) and SB 269970 (5-HT(7) antagonist; 2.5 and 25 µg). Altogether, these results indicate the local involvement of 5-HT(1), 5-HT(2) and 5-HT(6), especially 5-HT(1B) and 5-HT(2A), in the nociceptive response induced by 5-HT in mice, thus contributing to a better understanding of 5-HT role in the peripheral nociceptive processing. In addition, they also point to important species differences and the need of a wide evaluation of the peripheral nociceptive processing in mice as these animals have been increasingly used in studies investigating the cellular and molecular mechanisms mediating the nociceptive response.