tropisetron and Pain

Experimental studies suggest that paracetamol-induced analgesia is mediated via central serotonergic pathways and attenuated by 5-HT3-antagonists. However, clinical studies do not support this, and 5-HT3-antagonists are expected to reduce pain by blocking the descending pronociceptive pathway. The current project tested whether tropisetron attenuates analgesia by paracetamol. Two randomized, double-blind, crossover studies with 18 healthy male volunteers in each were performed. Pain stimuli were cold water immersion (cold pressor test), contact heat pain (study 1) and electrical stimulation (study 2). In both studies, tropisetron 5 mg i.v. or saline was administered, followed by paracetamol 2 g i.v. 30 min. later. Individual changes in heat and cold pain intensity, cold pain tolerance and unpleasantness were recorded. The same thresholds were also expressed as scores (% of the individual score at baseline). Additionally, previously published findings on the effects of paracetamol and its interaction with 5HT3-antagonists in human experimental pain models were reviewed. After calculation of the sensory and pain scores (%), tropisetron seemed to amplify the analgesic action of paracetamol. Paracetamol 2 g i.v. did not show any statistically significant analgesia in thermal tests (study 1), or differences in sensory, pain detection or moderate pain thresholds of the electrical stimulus (study 2). As paracetamol did not have a measurable analgesic effect in these tests, no conclusions can be drawn about the interaction between paracetamol and tropisetron. However, tropisetron may have an analgesic effect of its own. Clinicians should not avoid using these drugs together, unless larger clinical studies indicate otherwise.

Topics: Acetaminophen; Adult; Analgesics, Non-Narcotic; Animals; Cross-Over Studies; Double-Blind Method; Drug Interactions; Humans; Indoles; Male; Pain; Pain Threshold; Serotonin 5-HT3 Receptor Antagonists; Tropisetron; Young Adult

Experimental studies suggest that paracetamol-induced analgesia is mediated via central serotonergic pathways and attenuated by 5-HT3-antagonists. However, clinical studies do not support this, and 5-HT3-antagonists are expected to reduce pain by blocking the descending pronociceptive pathway. The current project tested whether tropisetron attenuates analgesia by paracetamol. Two randomized, double-blind, crossover studies with 18 healthy male volunteers in each were performed. Pain stimuli were cold water immersion (cold pressor test), contact heat pain (study 1) and electrical stimulation (study 2). In both studies, tropisetron 5 mg i.v. or saline was administered, followed by paracetamol 2 g i.v. 30 min. later. Individual changes in heat and cold pain intensity, cold pain tolerance and unpleasantness were recorded. The same thresholds were also expressed as scores (% of the individual score at baseline). Additionally, previously published findings on the effects of paracetamol and its interaction with 5HT3-antagonists in human experimental pain models were reviewed. After calculation of the sensory and pain scores (%), tropisetron seemed to amplify the analgesic action of paracetamol. Paracetamol 2 g i.v. did not show any statistically significant analgesia in thermal tests (study 1), or differences in sensory, pain detection or moderate pain thresholds of the electrical stimulus (study 2). As paracetamol did not have a measurable analgesic effect in these tests, no conclusions can be drawn about the interaction between paracetamol and tropisetron. However, tropisetron may have an analgesic effect of its own. Clinicians should not avoid using these drugs together, unless larger clinical studies indicate otherwise.

Topics: Acetaminophen; Adult; Analgesics, Non-Narcotic; Animals; Cross-Over Studies; Double-Blind Method; Drug Interactions; Humans; Indoles; Male; Pain; Pain Threshold; Serotonin 5-HT3 Receptor Antagonists; Tropisetron; Young Adult

Because the mechanism underlying the analgesic action of acetaminophen remains unclear, we investigated the possible interaction of acetaminophen with central serotonergic pathways. The effects of acetaminophen, tropisetron, the combination of both drugs, and saline on pain perception and central sensitization in healthy volunteers were compared. Sixteen healthy volunteers were included in this randomized, double-blind, placebo-controlled crossover study. Intracutaneous electrical stimulation (46.1 ± 19.1 mA) induced acute pain (numeric rating scale, 6 of 10) and stable areas of hyperalgesia and allodynia. Pain intensities and areas of hyperalgesia and allodynia were regularly assessed before, during, and after a 15-min infusion of acetaminophen, tropisetron, the combination of both drugs, and saline. Acetaminophen concentrations were measured to rule out any pharmacokinetic interaction. Both acetaminophen and tropisetron led to decreased pain ratings as compared to saline. However, when acetaminophen and tropisetron were administered simultaneously, the pain ratings were not affected. There was no significant difference in the evolution of the hyperalgesic and allodynic areas during the study period between the study groups (P = .06 and P = .33, respectively). Acetaminophen serum levels were not significantly different when associated with tropisetron (P = .063), although we observed a trend toward lower acetaminophen concentrations when both drugs were concurrently administered. In summary, while the combination of acetaminophen and tropisetron showed no analgesic action, each drug administered alone led to decreased pain ratings as compared to saline. In an electrically evoked human pain model, the combination of acetaminophen with tropisetron was free of any analgesic potential. However, when administered on its own, both acetaminophen and tropisetron were mildly analgesic.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Analysis of Variance; Anti-Inflammatory Agents; Cross-Over Studies; Double-Blind Method; Drug Interactions; Electric Stimulation; Forearm; Humans; Hyperalgesia; Indoles; Models, Theoretical; Pain; Pain Measurement; Pain Threshold; Physical Stimulation; Reaction Time; Time Factors; Tropisetron

Preclinical studies have suggested that the mechanism of the analgesic action of acetaminophen (INN, paracetamol) is linked to the serotonergic system and that it is inhibited by tropisetron, a 5-hydroxytryptamine type 3 antagonist. The aim of this study was to confirm these findings in humans.. Twenty-six rapid metabolizers of tropisetron were included in this double-blind crossover study. After ethical approval, at weekly intervals, the subjects took a single oral dose of 1 g acetaminophen combined with either intravenous tropisetron (5 mg), granisetron (3 mg), or placebo (saline solution). For each session, the analgesic effect of acetaminophen was assessed by use of a pain self-evaluation instrument, the Pain Matcher. The pain detection threshold was determined 5 times over the period of the 4 postdosing hours. The area under the curve (0-4 hours) (mean +/- SD) of acetaminophen/tropisetron and the area under the curve of acetaminophen/granisetron were compared with the effect of acetaminophen/placebo. Blood samples for acetaminophen concentration measurements were taken to evaluate a pharmacokinetic interaction.. The analgesic effect of acetaminophen/placebo (expressed as the area under the curve of the percentage of the individual pain score reported at baseline along time [% x min]) (2145 +/- 2901 % x min) was totally inhibited by both tropisetron (89 +/- 1747 % x min, P = .007) and granisetron (45 +/- 2020 % x min, P = .002). Acetaminophen concentration was not significantly different when associated with tropisetron (P = .919) or granisetron (P = .309).. These results clearly show for the first time in humans that the coadministration of tropisetron or granisetron with acetaminophen completely blocks the analgesic effect of acetaminophen. They support the hypothesis that the mechanism of the analgesic action of acetaminophen might involve the serotonergic system. Furthermore, they demonstrate a pharmacodynamic interaction between these 2 types of drugs, which are frequently coadministered, especially in cancer patients.

Topics: Acetaminophen; Adult; Analgesics, Non-Narcotic; Area Under Curve; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Granisetron; Humans; Indoles; Male; Pain; Pain Measurement; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Tropisetron

To determine the efficacy of a serotonin receptor (5-HT(3)) antagonist in the treatment of fibromyalgia (FM) in a prospective, randomized, double-blind, placebo-controlled, multicentre trial.. Twenty-one female patients (age 21-63 years) with FM according to the American College of Rheumatology classification criteria for FM were assigned randomly to either a placebo group or to receive a daily intravenous bolus injection of 5 mg tropisetron for 5 days.. In patients receiving tropisetron, the visual analogue scale (VAS) score for pain decreased by 28.9 compared with a decrease of 6.8 in the placebo group [probability (p)=0.063; effect size: 0.794]. Similar results were obtained using a body diagram pain score as a secondary efficacy parameter: mean pain reduction was 27.2 in the tropisetron group, versus 2.8 in the placebo group (p=0.038; effect size: 0.902).. 5-HT(3) receptor antagonists provide significant pain relief for a group of FM patients.

Topics: Adult; Double-Blind Method; Female; Fibromyalgia; Humans; Indoles; Middle Aged; Pain; Placebos; Serotonin Antagonists; Tropisetron

Central pain processing is altered in patients with fibromyalgia syndrome (FMS). The serotonin metabolism, especially the 5-HT3 receptor, seems to play an important role.. We investigated the effect of the local injection of the 5-HT3 receptor antagonist tropisetron on the perception and central processing of pain in FMS patients using painful mechanical stimulation and functional magnetic resonance imaging (fMRI) within the framework of a pre-/posttreatment double-blind design.. In the contralateral primary somatosensory cortex, contralateral posterior insula, and anterior cingulate cortex, we found that the activation was significantly reduced after treatment. On average, patients rated the stimulation-induced pain intensity as stronger in the session after treatment compared to before treatment, although the individual data revealed a heterogeneous pattern. All patients showed sensitisation during the painful stimulation, which was not influenced by the treatment.. Both the sensory-discriminative and motivational-affective components of pain as measured by fMRI were altered by tropisetron.

Topics: Brain; Female; Fibromyalgia; Humans; Indoles; Magnetic Resonance Imaging; Middle Aged; Pain; Pain Measurement; Pilot Projects; Receptors, Serotonin; Tropisetron

A comparison between a local anesthetic drug and the 5-hydroxytryptamine 3 (5-HT3) receptor antagonist tropisetron in treating tendopathies or periarthropathies revealed that tropisetron has a longer effect on resting pain and pain on movement than the local anesthetic drug. The most likely explanation for this effect probably is a blocking of stimulated 5-HT3 receptors at the nociceptors in conjunction with an inhibited release of substance P and other neurokines because of this blockage. Further studies will have to show whether the action of tropisetron in tendopathies is as favorable as that of corticosteroids.

Topics: Anesthetics, Local; Double-Blind Method; Female; Humans; Indoles; Infusions, Intralesional; Injections, Intra-Articular; Male; Middle Aged; Movement; Pain; Pain Measurement; Prilocaine; Serotonin Antagonists; Tendinopathy; Treatment Outcome; Tropisetron

To determine whether local injection of the 5-HT3-receptor antagonist, tropisetron. reduces pain in tendinopathies to the same degree as a local injection of corticosteroids in combination with local anesthetic.. Forty patients with tendinopathies were enrolled in this randomized, observer-blind study. An injection of either 5 mg tropisetron. or 10 mg dexamethasone combined with 60 mg lidocaine was administered around the affected tendon. The effect was measured with a visual analog pain scale before the injection, after 3 hours and on each of the following 7 days, in patients with good effects also 3 months after the injection.. There were no significant differences between the tropisetron and the corticosteroid/anesthetic group in terms of pain at rest or on movement during the study. Both treatments were well tolerated.. Local injection of tropisetron seems to be as safe and as effective as the combination of corticosteroids and local anesthetics in the treatment of painful tendinopathies.

Topics: Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Anesthesia, Local; Female; Humans; Indoles; Male; Middle Aged; Pain; Serotonin Antagonists; Severity of Illness Index; Single-Blind Method; Tendinopathy; Treatment Outcome; Tropisetron

MD-354 (m-chlorophenylguanidine) is a 5-HT3/alpha2B-adrenoceptor ligand. Both receptors play a role in antinociception. In the mouse tail-flick assay, subcutaneously administered MD-354 was inactive as an analgesic. However, a combination of an inactive dose of clonidine (0.25 mg/kg) with an inactive dose of MD-354 (6 mg/kg) produced a substantial antinociceptive effect (maximal possible effect=66%). Considering the 5-HT3 receptor partial agonist properties of MD-354, the analgesia enhancing effect of MD-354 on clonidine might be associated, at least in part, with its 5-HT3 receptor agonist or antagonist activity. Combinations of an inactive dose of clonidine (0.25 mg/kg) with 5-HT3 receptor antagonists (tropisetron, zacopride and ondansetron) were examined. Saline-like doses of tropisetron, zacopride and ondansetron significantly enhanced the antinociceptive effect of clonidine (combinations: maximal possible effect=86%, 82% and 79% respectively), suggesting that MD-354 may enhance the analgesic actions of clonidine, at least in part, through a 5-HT3 receptor antagonist mechanism.

Topics: Analgesics; Animals; Behavior, Animal; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Clonidine; Dose-Response Relationship, Drug; Drug Synergism; Guanidines; Indoles; Male; Mice; Mice, Inbred ICR; Models, Animal; Motor Activity; Ondansetron; Pain; Pain Measurement; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Time Factors; Tropisetron

Intraperitoneal injection of serotonin (5-HT; 0.5-4.0 mg/kg) produced dose-dependent nociceptive writhing responses, attenuated at all doses by pre-administration of tropisetron (1.0 mg/kg, i.p.). Administration of 2-methylserotonin (2-methyl-5-HT) alone was ineffective in inducing writhing. The effects of 5-HT (0.5 mg/kg, i.p.) were increased by subsequent injection of 2-methyl-5-HT (0.5-4.0 mg/kg, i.p.). The enhanced nociceptive responses produced by low dose of 5-HT and subsequently administered 2-methyl-5-HT were attenuated by pretreatment with tropisetron. These results suggest that the inflammatory cascade produced by peripheral administration of 5-HT evokes nociception by stimulating visceral 5-HT(3) receptors and that 5-HT-induced mechanisms appear to sensitize the 5-HT(3) receptor to subsequent pharmacologic activation.

Topics: Animals; Dose-Response Relationship, Drug; Drug Synergism; Indoles; Male; Mice; Pain; Pain Measurement; Receptors, Serotonin, 5-HT3; Serotonin; Serotonin 5-HT3 Receptor Agonists; Serotonin 5-HT3 Receptor Antagonists; Tropisetron

To characterize the immune modulatory effects of 5-HT3 receptor antagonist treatment in patients with fibromyalgia, autoimmune disorders, and chronic pain.. Multiplex-assisted cytokine measurements were performed before and during treatment. Whole blood stimulation with TNF-alpha was carried out to determine the proinflammatory response induced by exogenous TNF-alpha.. Five of nine patients clinically responded to treatment, and two had a moderate response. All patients had significantly elevated levels of T-H1 cytokines more prominent than TNF-alpha, IL-1beta, and IL-6. Treatment resulted in transient effects on peripheral monocyte counts in all but one patient, a plasma IL-1beta increase in two responder patients, and decreased T-H1 cytokines in two responder patients. Ex vivo TNF-alpha stimulation was transiently reconstituted in three responder patients to a significant level. Three patients showed a marginal reconstitutive response.. 5-HT3 receptor blockade transiently affects monocyte tissue infiltration, modulates T-H1 cytokines in clinical responders as well as MIP-1beta in moderate responders, and transiently affects the ex vivo response to exogenous TNF-alpha.

Topics: Adult; Aged; Autoimmune Diseases; Chronic Disease; Fibromyalgia; Humans; Immune System; Indoles; Middle Aged; Pain; Serotonin 5-HT3 Receptor Antagonists; Serotonin Antagonists; Tropisetron

Preliminary results of an ongoing study on the effectiveness of trigger point injections with tropisetron in 20 patients with late whiplash-associated disorder are presented. The study demonstrated more than 50% pain relief for more than 2 weeks in 52% of the 73 treatment sessions. The duration of effectiveness of the injections showed great intraindividual and interindividual variation.

Topics: Female; Humans; Indoles; Injections; Male; Pain; Serotonin 5-HT3 Receptor Antagonists; Serotonin Antagonists; Tropisetron; Whiplash Injuries

In 223 fibromyalgia (FM) patients in a rheumatology practice, a follow-up postal survey was carried out 0.5-2 years after a 5-day intravenous (i.v.) treatment with 5 mg of the 5-HT3 receptor antagonist tropisetron daily on the effect of this treatment. 121 patients returned the completed questionnaire. After subtraction of 22 undeliverable questionnaires, this represented 60.2% of patients contacted for whom an assessment of the tropisetron treatment was possible. A good to very good effect of the treatment on the pain was reported by 45% of the patients, and only 25% reported an unsatisfactory effect. The effect of tropisetron IV lasted between one day and 12 weeks (mean 8.6 +/- 13.6 d). Sleep and general condition were also assessed as good or very good by almost half of the patients. The tolerance of tropisetron was generally good. In comparison with the current treatment and the best treatment with other drugs ever received, tropisetron was rated as more efficacious in almost half of the cases, though an unsatisfactory effect of tropisetron compared to other treatments was reported in 30% of the cases. Considered in comparison to less or at most equally efficacious alternatives, according to this open respective study, IV tropisetron treatment represents a promising option for the treatment of FM even though the study design incorporated many imponderables. Particularly the question of whether the success of treatment can be improved further with a longer lasting treatment or a selection of the patients still needs to be settled.

Topics: Female; Fibromyalgia; Humans; Indoles; Injections, Intravenous; Male; Middle Aged; Pain; Retrospective Studies; Rheumatology; Serotonin 5-HT3 Receptor Antagonists; Serotonin Antagonists; Surveys and Questionnaires; Tropisetron

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

Formalin injected subcutaneously into the paw is a widely used model of pain. This procedure evokes a short-lasting period of flinching (phase 1) and a long-lasting period of intense flinching (phase 2) following a very short period of quiescence. Phase 2 has been extensively used to support the involvement of central (spinal cord) sensitization in inflammatory hyperalgesia. The present study evaluated the contribution of stimulation of peripheral nociceptors by the release of endogenous mediators at the site of lesion. The participation of histamine and 5-hydroxytryptamine was demonstrated by the treatment of the rat hindpaws with selective histamine H1 (pyrilamine and meclizine) and histamine H2 (cimetidine) receptor antagonists or selective 5-hydroxytryptamine(1A) (WAY100,135) and 5-hydroxytryptamine(4/3) (tropisetron) receptor antagonists. The co-administration of pyrilamine or meclizine with formalin (1%) significantly reduced phases 1 and 2, while cimetidine had no effect. Pyrilamine administration during the period of quiescence (10min after formalin administration) caused strong dose-related inhibition of phase 2. The co-administration of tropisetron with formalin caused a blockade of both phases, while with WAY100,135 caused only inhibition of the phase 2. In contrast, tropisetron administrated during the period of quiescence did not cause antinociception. Histamine and 5-hydroxytryptamine receptors could be strongly activated in naïve animals by administration of a mixture of both agonists or compound 48/80 (2microg/paw) which is known to release both mediators from mast cells. Pretreatment of the paws with a mast cell stabilizer, sodium cromoglycate, significantly reduced the second phase of the formalin injection model. From these results we suggest that phases 1 and 2 of the formalin test are dependent upon the ongoing afferent input. Furthermore, while histamine H1 participates in both phases, 5-hydroxytryptamine(4/3) participates in phase 1 and 5-hydroxytryptamine(1A) in phase 2.

Topics: Animals; Anti-Asthmatic Agents; Cimetidine; Cromolyn Sodium; Histamine; Histamine H1 Antagonists; Histamine H2 Antagonists; Indoles; Male; Meclizine; Neurons, Afferent; Nociceptors; p-Methoxy-N-methylphenethylamine; Pain; Pain Measurement; Piperazines; Pyrilamine; Rats; Rats, Wistar; Serotonin; Serotonin Antagonists; Tropisetron

We studied the effect of NAN-190 (5-HT(1A) antagonist), ketanserin (5-HT(2) antagonist) and ICS 205-930 (5-HT(3) antagonist) on tooth pulp stimulation (TPS)-induced 5-HT release and substance P (SP) release in the superficial layers of the trigeminal nucleus caudalis (SpVc-I,II) in the presence or absence of electro-acupuncture (EAP). TPS slightly increased 5-HT release and significantly increased SP release. In combination with EAP, TPS-induced 5-HT release was remarkably enhanced, whereas SP release was significantly suppressed. Pretreatment with NAN-190 (3.5 mg/kg, i.v.) significantly enhanced the increase in TPS-induced 5-HT release in the presence of EAP. On the other hand, the increase of 5-HT release induced following TPS in the presence of EAP was inhibited by pretreatment with ketanserin (2.5 mg/kg, i.v.) and ICS 205-930 (1 mg/kg, i.v.). When NAN-190 was pre-treated in the animals combined TPS and EAP, the amount of SP release was significantly reduced compared with the absence of this drug. On the other hand, pretreatment with ketanserin and ICS 205-930 reversed the inhibitory effect of EAP on the TPS-generated SP release, especially ICS 205-930, which remarkably enhanced TPS-induced SP release compared with the absence of this drug. On the basis of the obtained results, we concluded that NAN-190 and ICS 205-930 act on EAP-induced analgesia positively and suppressively, respectively, by regulation of TPS-generated SP release through activation of their subtype receptors. On the other hand, ketanserin does not affect TPS-induced 5-HT release and SP release in the presence of EAP.

Topics: Afferent Pathways; Animals; Dental Pulp Cavity; Electric Stimulation; Electroacupuncture; Indoles; Ketanserin; Male; Neurons; Nociceptors; Pain; Pain Management; Piperazines; Rabbits; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Substance P; Trigeminal Caudal Nucleus; Tropisetron

The analgesic effect of calcitonin when serotonin (5-HT) concentration is increased and the involvement of some 5-HT receptors were studied using the writhing test in mice. 5-hydroxytryptophan (5-HTP) administration increased both 5-HT levels in the central nervous system (CNS) and calcitonin analgesia. The 5-HT(1A) agonist (+/-)-8-hydroxy-2-dipropylaminotetralin hydrobromide (8-OH-DPAT) diminished calcitonin analgesia, this effect being antagonised by the 5-HT(1A) antagonist (WAY 100, 135). As the stimulation of 5-HT(1A) autoreceptors reduces the turnover of 5-HT, the effect of 8-OH-DPAT on calcitonin analgesia may be attributed to this decrease. The 5-HT(2A-2C) agonist (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI) diminished calcitonin analgesia. A sub-analgesic dose of the 5-HT(2A) antagonist ketanserin failed to prevent this effect. The 5-HT(3) agonist (+/-)-2-methyl-5-hydroxytryptamine maleate (2-methyl-5-HT) potentiated calcitonin analgesia, whereas it was significantly reduced by the 5-HT(3) antagonist tropisetron. The effect of 2-methyl-5-HT on calcitonin analgesia was also reversed by tropisetron, This result suggests that the 5-HT(3) receptor may play an important role in the relationship between calcitonin and the serotonergic system. Tropisetron also reversed the analgesia induced by calcitonin plus 5-HTP corroborating importance of the 5-HT(3) receptors.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Analgesics; Animals; Brain Chemistry; Calcitonin; Dose-Response Relationship, Drug; Indoles; Indophenol; Ketanserin; Male; Mice; Mice, Inbred Strains; Nociceptors; Pain; Pain Measurement; Piperazines; Pyridines; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Tropisetron

1. Activation of abdominal sympathetic afferents during ischaemia reflexly excites the cardiovascular system. We have shown previously that exogenous 5-hydroxytryptamine (5-HT, i.e. serotonin) stimulates abdominal sympathetic afferent nerve endings, and recently have documented increased concentrations of 5-HT in intestinal lymph and portal venous plasma during brief abdominal ischaemia. The present investigation evaluated the role of endogenously produced 5-HT in activation of ischaemically sensitive abdominal sympathetic afferents. 2. Nerve activity of single-unit C fibre afferents innervating duodenum, mesentery, pancreas, portal hepatis, bile duct, gall bladder and jejunum was recorded from the right thoracic sympathetic chain of anaesthetized cats. Ischaemically sensitive C fibre afferents were identified according to their response to 5-10 min of abdominal ischaemia. 3. Intra-arterial injection of 5-HT (20 microg kg-1) increased discharge activity of twelve afferents from 0. 23 +/- 0.05 to 0.96 +/- 0.09 impulses s-1 after an onset latency of 5.7 +/- 1.4 s. Also, 2-methylserotonin (100 microg kg-1, i.a.), a 5-HT3 receptor agonist, stimulated eleven of twelve afferents to significantly increase their discharge activity from 0.25 +/- 0.05 to 0.90 +/- 0.10 impulses s-1 after a latency of 3.3 +/- 0.4 s. Furthermore, intravenous injection of tropisetron (200 microg kg-1), a 5-HT3 receptor antagonist, significantly attenuated the increase in activity of twelve other C fibre afferents during 10 min of abdominal ischaemia from 1.62 +/- 0.18 to 0.94 +/- 0.22 impulses s-1, and eliminated the response of eleven other afferents to 5-HT. 4. Both the 5-HT2 receptor agonist, alpha-methylserotonin (100 microg kg-1, i.a.), and the 5-HT1 receptor agonist, 5-carboxamidotryptamine (100 microg kg-1, i.a.), did not alter the impulse activity of these twelve afferents (0.29 +/- 0.05 to 0.31 +/- 0.06, and 0.26 +/- 0.06 to 0.29 +/- 0.06 impulses s-1, respectively). 5. Treatment with indomethacin (5 mg kg-1, i.v.) in eight different cats did not alter the response of nine C fibre afferents to exogenous 5-HT (0.91 +/- 0. 17 vs. 1.19 +/- 0.25 impulses s-1, P > 0.05). 6. The results suggest that, during mesenteric ischaemia, endogenous 5-HT contributes to the activation of abdominal sympathetic afferents, mainly through direct stimulation of 5-HT3 receptors and that the action of 5-HT on these afferents appears to be independent of the cyclo-oxygenase pathway.

Topics: Adrenergic Fibers; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cats; Electrophysiology; Female; Ganglia, Sympathetic; Indoles; Indomethacin; Ischemia; Male; Neurons, Afferent; Pain; Prostaglandins; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Splanchnic Circulation; Tropisetron; Viscera

We examined the effects of intravenous injection of several serotonin (5-HT) antagonists on the inhibitory action of electro-acupuncture (EAP) against the nociceptive responses in the trigeminal nucleus caudalis in rabbits. The inhibitory effect of EAP was suppressed by pindolol, methysergide and ICS 205-930, whereas NAN-190 and ketanserin amplified the EAP effect. These results suggest that 5-HT1, except 5-HT1A; 5-HT2, except 5-HT2A; and 5-HT3 receptors are positively involved in EAP-induced analgesia, whereas the activation of 5-HT1A and 5-HT2A receptors suppressively act on EAP-induced analgesia.

Topics: Animals; Dental Pulp; Electric Stimulation; Electroacupuncture; Evoked Potentials; Indoles; Injections, Intravenous; Ketanserin; Male; Methysergide; Nociceptors; Pain; Pindolol; Piperazines; Rabbits; Receptors, Serotonin; Serotonin Antagonists; Trigeminal Caudal Nucleus; 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

We tested the antinociceptive effect of intrathecal (i.t.) administration of 5-HT3 and the 5-HT3 receptor agonist, 1-(m-chlorophenyl)-biguanide (mCPBG), in rats submitted to a mechanical noxious stimulus and the influence of the 5-HT3 receptor selective antagonists, tropisetron and granisetron. Both 5-HT and mCPBG (0.01, 0.1, 1, 10, 20 micrograms/rat) produced a significant dose-dependent antinociception. The lowest active doses were 0.1 and 1 microgram for 5-HT and mCPBG, respectively. The effect, observed with 20 micrograms, was significantly lower with mCPBG (+33 +/- 6%) than with 5-HT (+63 +/- 7%). For 5-HT-induced antinociception, the minimal inhibitory doses were 0.001 micrograms/rat for tropisetron and 10 micrograms/rat for granisetron. In contrast, the same doses of the two antagonists (from 0.1 microgram/rat) similarly inhibited the effect of mCPBG. This study provides evidence that contrary to tropisetron, doses of granisetron able to inhibit the effect of a 5-HT3 receptor agonist failed to reduce that of 5-HT. This demonstrates a heterogeneity between 5-HT3 receptor antagonists and questions the true involvement of these receptors in spinal 5-HT-induced antinociception.

Topics: Animals; Biguanides; Dose-Response Relationship, Drug; Granisetron; Indoles; Male; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Sensory Thresholds; Serotonin Antagonists; Serotonin Receptor Agonists; Spinal Cord; Tropisetron

Intraplantar co-administration of sub-anesthetic doses of bupivacaine (2.5 microg) or lidocaine (7.5 microg) increased the dose- and time-dependent analgesic effects of the 5-HT3 receptor antagonist, 3-a-tropanyl-1-H-indole-3-carboxylic ester (ICS-205 930) (1-100 microg; 50 microl) against inflammatory pain induced by hindpaw inoculation with complete Freund's adjuvant. The effects of bupivacaine were greater than lidocaine at all doses of ICS-205 930 tested. These findings may reflect facilitation of ICS-205 930 effects through negative allosteric modulation by bupivacaine and lidocaine of peripheral 5-HT3 receptors involved in nociceptive processing.

Topics: Analgesia; Anesthetics, Local; Animals; Bupivacaine; Drug Synergism; Indoles; Inflammation; Lidocaine; Male; Pain; Pain Measurement; Rats; Serotonin Antagonists; Tropisetron

Subcutaneous administration of granisetron (BRL 43694, endo-1-methyl-N-(9-methyl-9-azabicyclo[3.3.1.]non-3-yl-1 H-indazole-3-carboxamide) and zacopride (4-amino-N-(1-azabicyclo[2.2.2.]oct-3-yl)-5-chloro-2-methoxybenzamide), two 5-HT3 receptor antagonists, at doses ranging from 3 to 1000 micrograms/kg, inhibited abdominal contractions induced by distension (30 mmHg, 10 min) of irritated colon (0.6% acetic acid) in conscious rats with a bell-shaped dose-response curve. The ED50 of granisetron and zacopride were 17.6 and 8.2 micrograms/kg, respectively. In contrast, both tropisetron (ICS 205-930, (3-a-tropanyl)t-indole-3-carboxylic ester) and ondansetron (GR38032F, 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1 H-imidazol-1-yl)methyl]-4 H-carbazol-4-one hydrocloride dihydrate) were inactive in this model. These data further support the concept of a heterogeneity in the potency of 5-HT3 receptor antagonists in modulating visceral hypersensitivity in conscious rats. This finding is in agreement with a reported efficacy of granisetron but not of ondansetron in patients with irritable bowel syndrome.

Topics: Animals; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Colon; Granisetron; Indoles; Male; Muscle Contraction; Muscle, Smooth; Ondansetron; Pain; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Tropisetron

Tiapride dose-dependently attenuated the biphasic nociceptive responses induced by s.c. injection of formalin to the hindpaw of mice, and its activity on the first (ED50 = 110 mg/kg p.o.) and the second (ED50 = 32.0 mg/kg p.o.) phases paralleled that on the nociceptive response to intrathecal injection of substance P (ED50 = 190 mg/kg p.o.) and somatostatin (ED50 = 56.0 mg/kg p.o.), respectively. Moreover, a similar antinociceptive activity was observed in streptozotocin-induced diabetic or genetically diabetic (db/db) mice. The effects of tiapride (100 mg/kg p.o.) on both phases of the formalin test in normal mice were abolished by pretreatment with p-chlorophenylalanine (800 x 2 mg/kg p.o.), a 5-hydroxytryptamine (5-HT) depletor, or pindolol (1 mg/kg i.p.), a 5-HT1 antagonist, but were scarcely affected by 3-tropanyl-indole-3-carboxylate, a 5-HT3 antagonist. Ketanserin (1 mg/kg i.p.), a 5-HT2 antagonist, attenuated the effect of tiapride on the second phase but not on the first phase. This study on the antinociceptive mechanism of action of tiapride (that blocks painful neuropathy in diabetic patients) has led us to hypothesize that the drug attenuates pain transmission through an indirect activation of central 5-HT1 and 5-HT2 receptors.

Topics: Animals; Central Nervous System; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dopamine Antagonists; Female; Fenclonine; Indoles; Injections, Spinal; Ketanserin; Male; Mice; Nociceptors; Pain; Pain Measurement; Pindolol; Serotonin; Serotonin Antagonists; Somatostatin; Substance P; Synaptic Transmission; Tiapamil Hydrochloride; Tropisetron

Recent studies have shown that non-opioid defensive analgesia in male mice is potently inhibited by the 5-HT3 receptor antagonist, ondansetron. The present series of experiments was conducted to further explore the involvement of 5-HT3 receptor mechanisms in this particular form of adaptive inhibition of pain. The drug ICS 205-930 significantly attenuated the reaction at 1.25-2.5 micrograms/kg, with smaller and larger doses being ineffective. Both MDL 72222 and MDL 73147EF produced flat dose-response curves, with significant inhibition of defensive analgesia at minimum effective doses of less than or equal to 10 and 300 micrograms/kg, respectively. Although MDL 72699, the quaternary salt of MDL 72222, also inhibited the reaction, this effect was seen at comparatively large doses (0.5-1.0 mg/kg) only. None of the compounds tested had significant intrinsic effects of tail-flick latencies, over the dose ranges tested. These findings indicate that 5-HT3 receptor mechanisms may have an important modulatory role in certain forms of "stress" analgesia. Data are discussed in relation to the consistent profile of partial inhibition produced by 5-HT3 receptor antagonists in this model.

Topics: Analgesia; Analysis of Variance; Animals; Dose-Response Relationship, Drug; Hot Temperature; Indoles; Male; Mice; Mice, Inbred DBA; Pain; Posture; Quinolizines; Receptors, Serotonin; Reference Values; Serotonin Antagonists; Stereotyped Behavior; Tropanes; Tropisetron

1. Distension of the duodenum in anaesthetized rats, by rapid application of intraluminal pressures (10-75 cmH2O), evoked falls in diastolic blood pressure and intragastric pressure. 2. The distension-induced responses were blocked by pretreatment with morphine (20 mg kg-1, s.c.), an action reversible by injection of naloxone (5 mg kg-1, i.v.). 3. Bilateral cervical vagotomy reduced the distension-evoked fall in intragastric pressure but had no effect on the corresponding fall in blood pressure. 4. Granisetron or ICS 205-930 (1-1000 micrograms kg-1, i.v.) had no effects on duodenal intraluminal pressure, but reduced the responses to distension with a bell-shaped dose-response relationship. Ondansetron (1-1000 micrograms kg-1, i.v.) did not reduce the reflex responses. 5. These results show that the 5-HT3 receptor antagonists used exerted different effects on the reflex responses to duodenal distension.

Topics: Animals; Blood Pressure; Duodenum; Granisetron; Imidazoles; Indazoles; Indoles; Male; Morphine; Muscle Contraction; Muscle, Smooth; Ondansetron; Pain; Pyrazoles; Rats; Rats, Inbred Strains; Reflex; Serotonin Antagonists; Stomach; Tropisetron; Vagotomy

The effect of ICS 205-930 (ICS), a specific 5-HT3 receptor antagonist, was analyzed on the sensitization of ventrobasal (VB) thalamic neuronal responses produced by an intraplantar injection of carrageenin. ICS was injected locally in the plantar paw, simultaneously, or after carrageenin (at 20 min or later than 70 min). The progressive increase of the VB neuronal responses to pinch (total number of spikes in the discharge) due to carrageenin sensitization, was prevented, blocked, or reversed, by intraplantar ICS, at a dose as low as 3.2 ng/kg, when injected, simultaneously or in the first half-hour following the carrageenin injection itself. The carrageenin sensitization then reappeared, 50-90 min after the initiation of the inflammation. By contrast to these early injections of ICS, a later administration of ICS (70 min or more, after the carrageenin injection), did not influence the sensitization. The time course of the effects of this 5-HT3 antagonist receptor agrees well with the time course of 5-HT release into the inflammatory exudate. These data, and those previously reported on the action of aspirin and of a peripheral antihistamine on carrageenin sensitization, are compared. These results indicate the relative participation of the various inflammatory substances released in the exudate, and the importance of timing of administration for an effective antagonism of the hyperalgesia elicited by this inflammation.

Topics: Action Potentials; Animals; Carrageenan; Indoles; Inflammation; Male; Pain; Peripheral Nerves; Rats; Rats, Inbred Strains; Receptors, Serotonin; Sensory Thresholds; Thalamic Nuclei; Tropisetron

The ability of the highly selective 5-HT3 receptor antagonist ICS 205-930 (3 alpha-tropanyl-1H-indole-3-carboxylic acid ester) to block the increase in tail flick (TFL) and hot plate latencies (HPL) produced by intrathecally (i.t.) administered serotonin (5-HT) was examined in pargyline pretreated rats. ICS 205-930 (0.1 microgram, i.t.) blocked the ability of 5-HT (200 micrograms) to increase TFL and HPL. Significant hyperalgesia, as measured by a decrease in TFL and HPL compared to saline controls, also resulted from either the coadministration of ICS 205-930 (10 micrograms) and 5-HT (200 micrograms) or from ICS 205-930 (100 micrograms) alone. These data suggest an important role for 5-HT3 receptors in modulating spinal nociceptive responses.

Topics: Animals; Indoles; Injections, Spinal; Male; Nociceptors; Pain; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin; Spinal Cord; Tropisetron