Toluene exposure enhances acute and chronic formalin-induced nociception in rats: Participation of 5-HT3 receptors.

The purpose of this study was to evaluate the effect of acute toluene exposure on formalin (0.5% and 1%)-induced acute and long-lasting nociceptive hypersensitivity in rats. In addition, we sought to investigate the role of peripheral 5-HT3 receptors in the pronociceptive effect of toluene. Toluene exposure (6000ppm) for 30min enhanced 0.5% or 1% formalin-induced acute nociception and long-lasting secondary allodynia and hyperalgesia. In contrast, exposition to toluene for 30min in rats previously injected (six days before) with 1% formalin did not affect long-lasting hypersensitivy. Local peripheral pre-treatment with alosetron (5-HT3 receptor antagonist, 10-100 nmol) reduced the pronociceptive effect of toluene in acute nociception and long-lasting secondary allodynia and hyperalgesia. Alosetron (100nmol) was also able to reduce the nociceptive effects of 1% formalin in absence of toluene. Moreover, local peripheral injection of m-CPBG (5-HT3 receptor agonist, 300 nmol) enhanced 0.5% formalin-induced acute and long-lasting nociception in air- and toluene-exposed rats. Alosetron (10nmol) blocked the pronociceptive effects of m-CPBG (300nmol) on 0.5% formalin-induced acute and long-lasting hypersensitivity in rats exposed to toluene. Alosetron (at 10nmol) did not modify formalin-induced nociceptive behaviors. Finally, local peripheral pre-treatment with methiothepin (non-selective 5-HT receptor antagonist, 1.5nmol), did not affect the pronociceptive effect of toluene on 1% formalin-induced acute and long-lasting hypersensitivity. Our data demonstrate that acute exposure to toluene has pronociceptive effects in formalin-induced acute nociception and long-lasting hypersensitivity. Our data suggest that this pronociceptive effect depend on activation of peripheral 5-HT3, but not methiothepin-sensitive 5-HT, receptors.

Combination of diacerhein and antiepileptic drugs after local peripheral, and oral administration in the rat formalin test.

Preclinical Research The present study was designed to evaluate the possible antinociceptive interaction between diacerhein and some antiepileptic drugs (carbamazepine, topiramate and gabapentin) on formalin-induced nociception. Diacerhein, each of the antiepileptics or a fixed dose-ratio combination of these drugs was assessed after local peripheral and oral administration in rats. lsobolographic analyses were used to define the interaction between drugs. Diacerhein, antiepileptic drugs (carbamazepine, topiramate and gabapentin) or their combinations yielded a dose-dependent antinociceptive effect when administered by both routes. Theoretical ED30 values for the combination estimated from the isobolograms were obtained as follows: diacerhein-carbamazepine (85.99 ± 7.07 µg/paw; 56.53 ± 4.56 mg/kg po), diacerhein-topiramate (197.97 ± 22.90 µg/paw; 13.06 ± 2.44 mg/kg po) and diacerhein-gabapentin (96.87 ± 17.73 µg/paw; 17.90 ± 4.70 mg/kg p.o.) for the local peripheral and oral administration routes, respectively. These values were significantly higher than the experimentally obtained ED30 values: diacerhein-carbamazepine (49.33 ± 3.37 µg/paw; 35.49 ± 7.91 mg/kg po), diacerhein-topiramate (133.00 ± 39.10 µg/paw; 8.87 ± 1.46 mg/kg po) and diacerhein-gabapentin (70.98 ± 14.73 µg/paw; 10.95 ± 3.23 mg/kg po). The combinations produced their antinociceptive effects without motor impairment in the rotarod test indicating synergistic interactions with a good side effect profile.

Synergistic interaction between gabapentin and metamizol in the rat formalin test.

The purpose of this study was to assess the possible synergistic interaction between gabapentin and metamizol in the rat formalin test. Female Wistar rats were injected into the dorsal surface of the right hind paw with 50 microl of diluted formalin (1%). Formalin injection induced a typical flinching behavior indicating nociception. Reduction of the number of flinches was considered as antinociception. Gabapentin (10-300 mg/kg), metamizol (30-600 mg/kg), or the combination of gabapentin and metamizol were administered orally and the antinociceptive effect in the formalin test was determined. Isobolographic analyses were used to define the nature of the functional interaction between gabapentin and metamizol in a fixed-dose ratio (0.5:0.5). Gabapentin (ED30 18.3+/-7.9 mg/kg), metamizol (ED30 139.2+/-6.2 mg/kg) and fixed-dose ratio gabapentin-metamizol combinations dose-dependently reduced flinching behavior during second phase of the test. Theoretical ED30 value for the combination estimated from the isobologram was 78.8+/-5.5 mg/kg, whereas that experimental ED30 value was 15.0+/-1.2 mg/kg. Results indicate that oral administration of gabapentin and metamizol can interact synergistically to reduce inflammatory pain in the formalin test and suggest the use of this combination to relieve pain in humans.