tropisetron and Edema

Experiments were performed in carrageenin-treated rats to study, the antinociceptive and anti-inflammatory effects of paracetamol intravenously (i.v.) or intrathecally (i.t.) injected on rats submitted to a mechanical noxious stimulus. The influence of intrathecal tropisetron, a 5 hydroxytryptamine(3) (5-HT(3)) receptor antagonist, on the antinociceptive effects of paracetamol, was also studied. Paracetamol induced a significant antinociceptive effect after (100, 200 and 300 mg/kg) i.v. and (50, 100 and 200 microg/rat) i.t. injection, but no change occurred on edema volume. The effect of paracetamol was totally inhibited by tropisetron (10 microg/rat, i.t.). The foregoing results demonstrate that, in conditions of inflammatory pain, paracetamol exerts a central antinociceptive effect involving spinal 5-HT(3) receptors, without inducing any anti-inflammatory action. These data, give further arguments to consider paracetamol as a central analgesic drug which must be distinguished from non-steroidal anti-inflammatory drugs (NSAIDs), which justifies the usual combination of paracetamol in post-operative pain.

Topics: Acetaminophen; Animals; Anti-Inflammatory Agents, Non-Steroidal; Drug Interactions; Edema; Indoles; Inflammation; Injections, Intravenous; Injections, Spinal; Male; Pain; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Tropisetron

The role of 5-hydroxytryptamine and its receptor subtypes in the development of acute inflammation was investigated using the rat paw formalin test as a model for pain (measured by flinching behavior) and edema formation (measured by plethysmometry). The role of endogenously released 5-hydroxytryptamine was assessed using 5-hydroxytryptamine receptor subtype-selective antagonists co-injected with 2.5% formalin, while the receptor subtypes involved in the inflammatory process were further defined by co-injection of 5-hydroxytryptamine or 5-hydroxytryptamine receptor subtype-selective agonists with 0.5% formalin in anticipation of an augmented response. When co-administered with 2.5% formalin, propranolol, tropisetron or GR113808A, but not ketanserin, effectively blocked nociceptive behavior. In the presence of 0.5% formalin, 5-carboxamidotryptamine, 1-(m-chlorophenyl) biguanide or 5-methoxytryptamine, but not (+/-)-1-4-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane, augmented the flinching response. These data suggest involvement of 5-hydroxytryptamine1, 5-hydroxytryptamine3 and 5-hydroxytryptamine4 receptors in peripheral nociception. There may be some dissociation of nociception and edema formation, since no single 5-hydroxytryptamine receptor antagonist inhibited edema formation with 2.5% formalin; however, with 0.5% formalin, edema formation was enhanced by co-administration of 5-hydroxytryptamine, 5-carboxamidotryptamine, (+/-)-1-4-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane or 5-methoxytryptamine, but not 1-(m-chlorophenyl) biguanide. These data suggest involvement of 5-hydroxytryptamine1, 5-hydroxytryptamine2 and possibly 5-hydroxytryptamine4 receptors in edema formation. These results confirm the involvement of 5-hydroxytryptamine1 and 5-hydroxytryptamine3 receptor subtypes in peripheral nociception associated with acute inflammation and further suggest an involvement of the more recently characterized 5-hydroxytryptamine4 receptor in this process. There appears to be a dissociation in 5-hydroxytryptamine receptors involved in peripheral nociception and edema formation.

Topics: Animals; Edema; Formaldehyde; Indoles; Inflammation; Ketanserin; Male; Pain; Propranolol; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Tropisetron

The effect of ICS 205-930 (ICS), a specific 5-HT3 antagonist, was studied on carrageenan (CAR)-induced rat paw inflammation to assess the involvement of endogenous released serotonin (5-HT) in the observed hyperalgesia. Studies were performed using a behavioural test, measuring the threshold stimulus necessary to elicit vocalization by gradually increasing pressure applied to the paw. When administered (s.c., in the CAR-injected paw) either 20 min before, simultaneously or 20 min after CAR, ICS (10(-11) mol/kg, i.e., 3.2 ng/kg) completely prevented the hyperalgesia in both the injected and non-injected hind paws. This effect was prolonged for 90 min, equivalent to the effect on CAR on 5-HT release. Moreover, ICS increased the vocalization threshold over the pre-drug values in normal and CAR-treated rats when injected both 20 min before and simultaneously with the polysaccharide. On the contrary, it did not reduce the hyperalgesia, when injected 2 h after CAR. ICS had no effect at any time of administration on paw oedema. These results suggest that the early inflammatory sensitization of peripheral nociceptors is mainly dependent on the release of serotonin and that the hyperalgesic effect of the monoamine involves 5-HT3(M) receptors which do not seem to be involved in the early development of oedema.

Topics: Animals; Carrageenan; Differential Threshold; Edema; Hindlimb; Hyperalgesia; Hyperesthesia; Indoles; Male; Physical Stimulation; Rats; Rats, Inbred Strains; Serotonin Antagonists; Tropisetron; Vocalization, Animal