cgs-12066b and 5-carboxamidotryptamine

Although serotonin has been shown to inhibit peripheral sympathetic outflow, serotonin regulation on renal sympathetic outflow has not yet been elucidated. This study investigated which 5-HT receptor subtypes are involved. Wistar rats were anesthetized (sodium pentobarbital; 60mg/kg, i.p.), and prepared for in situ autoperfused rat kidney, which allows continuous measurement of systemic blood pressure (SBP), heart rate (HR) and renal perfusion pressure (PP). Electrical stimulation of renal sympathetic nerves resulted in frequency-dependent increases in PP (18.3±1.0, 43.7±2.7 and 66.7±4.0 for 2, 4 and 6Hz, respectively), without altering SBP or HR. 5-HT, 5-carboxamidotryptamine (5-HT1/7 agonist) (0.00000125-0.1μg/kg each) or l-694,247 (5-HT1D agonist; 0.0125μg/kg) i.a. bolus inhibited vasopressor responses by renal nerve electrical stimulation, unlike i.a. bolus of agonists α-methyl-5-HT (5-HT2), 1-PBG (5-HT3), cisapride (5-HT4), AS-19 (5-HT7), CGS-12066B (5-HT1B) or 8-OH-DPAT (5-HT1A) (0.0125μg/kg each). The effect of l-694,247 did not affect the exogenous norepinephrine-induced vasoconstrictions, whereas was abolished by antagonist LY310762 (5-HT1D; 1mg/kg) or l-NAME (nitric oxide; 10mg/kg), but not by indomethacin (COX1/2; 2mg/kg) or glibenclamide (ATP-dependent K(+) channel; 20mg/kg). These results suggest that 5-HT mechanism-induced inhibition of rat vasopressor renal sympathetic outflow is mainly mediated by prejunctional 5-HT1D receptors via nitric oxide release.

Topics: Animals; Blood Pressure; Heart Rate; Kidney; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Norepinephrine; Oxadiazoles; Quinoxalines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Serotonin; Serotonin 5-HT1 Receptor Antagonists; Sympathetic Nervous System; Synaptic Transmission; Tryptamines

1. In the present study, we analysed the effect of different doses of 5-hydroxytryptamine (5-HT; intravenous infusions of 0.001-40 microg/kg per min) in the autoperfused hindquarters of the rat subjected to electrical stimulation (frequencies of 0.5-20 Hz) of the lumbar chains, investigating the relationship between the adrenergic and serotonergic systems in this vascular bed. 2. Because we observed that 5-HT inhibited the increases in perfusion pressure induced by electrical stimulation of the lumbar chains, we used different agonists and antagonists to analyse the mechanism of action of 5-HT. 3. The effect of 5-HT was inhibited by methiothepin (a non-specific 5-HT receptor antagonist), but not by ritanserin (a selective 5-HT2 receptor antagonist). The effects of 5-HT were mimicked by 5-carboxamidotryptamine (a 5-HT1 receptor agonist) and L-694 247 (a selective 5-HT1D receptor agonist), but not by 8-hydroxy-2-dipropylaminotetralin (a 5-HT1A receptor agonist), CGS-12066B (a 5-HT1B receptor agonist), alpha-methyl-5-HT (a 5-HT2 receptor agonist), 1-(3-chlorophenyl) piperazine (a 5-HT2C receptor agonist) or 1-phenylbiguanide (a 5-HT3 receptor agonist). The selective 5-HT1D/1B receptor antagonist BRL 15572 inhibited the effect of the agonist L-694 247. 4. Our data suggest that 5-HT inhibits the increases in perfusion pressure induced by the electrical stimulation of the lumbar chains, acting on presynaptic 5-HT1D receptors and decreasing the release of noradrenaline from the sympathetic nerves in the hindquarter vascular bed of the rat.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Biguanides; Biphenyl Compounds; Dose-Response Relationship, Drug; Electric Stimulation; Hindlimb; In Vitro Techniques; Infusions, Intravenous; Male; Methiothepin; Oxadiazoles; Perfusion; Piperazines; Pressure; Quinoxalines; Rats; Rats, Wistar; Ritanserin; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT3 Receptor Agonists; Serotonin Agents; Serotonin Antagonists; Serotonin Receptor Agonists; Tryptamines; Vasoconstriction

5-hydroxytryptamine (5-HT) is released in spinal cord by descending systems that modulate somatosensory transmission and can potently depress primary afferent-evoked synaptic responses in dorsal horn neurons. Since primary afferent activity-induced long-term potentiation (LTP) may contribute to central sensitization of nociception, we studied the effects of 5-HT on the expression of sensory-evoked LTP and long-term depression (LTD) in deep dorsal horn (DDH) neurons. Whole cell, predominantly current clamp, recordings were obtained from DDH neurons in transverse slices of neonatal rat lumbar spinal cord. The effect of 5-HT on dorsal-root stimulation-evoked synaptic responses was tested before, during, or after high-frequency conditioning stimulation (CS). In most cells (80%), 5-HT caused a depression of the naïve synaptic response. Even though 5-HT depressed evoked responses, CS in the presence of 5-HT was not only still capable of inducing LTD but also increased its incidence from 54% in controls to 88% (P < 0.001). Activation of ligands selective for 5-HT(1A/1B) and 5-HT(1B), but not 5-HT(2A/2C) or 5-HT(3) receptors, best reproduced these actions. 5-HT also potently depressed postconditioning synaptic responses regardless of whether the induced plasticity was LTP or LTD. Our results demonstrate that in addition to depressing the amplitude of evoked sensory input, 5-HT can also control the direction of its long-term modifiability, favoring the expression of LTD. These findings demonstrate cellular mechanisms that may contribute to the descending serotonergic control of nociception.

Topics: Afferent Pathways; Amphetamines; Animals; Animals, Newborn; Biguanides; Boron Compounds; Excitatory Postsynaptic Potentials; Long-Term Potentiation; Methacrylates; Methylmethacrylates; Nerve Tissue Proteins; Neuronal Plasticity; Patch-Clamp Techniques; Posterior Horn Cells; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1B; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin; Serotonin Receptor Agonists; Single-Blind Method; Synaptic Transmission

The changes in the latency for tail withdrawal in response to noxious heating of the skin induced by microinjection of opioid or serotonergic agonists into the anterior pretectal nucleus (APtN) was studied in rats. The mu-opioid agonist DAMGO (78 and 156 picomol), but not the delta-opioid agonist DADLE (70 and 140 pmol), the kappa-opioid agonist bremazocine (0.24 and 0.48 nanomol) or the sigma-opioid agonist N-allylnormetazocine (0.54 nanomol), produced a dose-dependent antinociceptive effect. The 5-HT1 agonist 5-carboxamidotryptamine (19 and 38 nanomol) and the 5-HT1B agonist, CGS 12066B (1.12 and 2.24 nanomol), but not the non-selective 5-HT agonist m-CPP (41 to 164 nanomol), 5-HT2 agonist alpha-methylserotonin (36 and 72 nanomol) and 5-HT3 agonist 2-methylserotonin (36 and 72 nanomol), produced a dose-dependent antinociceptive effect. These results indicate that the antinociceptive effects of opioid or serotonergic agonists microinjected into the APtN depend on drug interaction with local mu or 5-HT1B receptors, respectively.

Topics: Analgesics; Animals; Benzomorphans; Brain; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine-2-Alanine; Enkephalins; Male; Microinjections; Pain; Phenazocine; Piperazines; Quinoxalines; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Serotonin; Serotonin Receptor Agonists

The effect of the serotonergic receptor agonist 1-(m-trifluoromethylphenyl)piperazine (TFMPP) was studied on the K(+)-evoked [3H]acetylcholine [( 3H]ACh) release from guinea pig hippocampal synaptosomes loaded with [3H]choline. TFMPP (5-1,000 microM) inhibited the evoked ACh release in a dose-dependent manner (IC50 = 81.8 microM). The inhibitory effect of TFMPP was mimicked by CGS-12066B (10, 30, and 100 microM), a 5-hydroxytryptamine1B (5-HT1B)/5-HT1D receptor agonist; 1-(m-chlorophenyl)piperazine (100 microM), a 5-HT1C/5-HT1B receptor agonist; and 5-carboxamidotryptamine (10 microM), a nonselective 5-HT1 receptor agonist. 8-Hydroxy-2-(di-n-propylamino)tetralin (10 and 100 microM), a 5-HT1A receptor agonist, and quipazine (10 and 100 microM), a 5-HT2 receptor agonist, did not have any significant effect. Serotonergic antagonists, such as dihydroergotamine (0.1 and 1 microM), metergoline (0.1 microM), methysergide (0.5 and 1 microM), or yohimbine (1 and 10 microM), blocked the TFMPP effect dose-dependently. In contrast, methiotepine (0.3 and 1 microM), propranolol (1 microM), ketanserin (0.1 microM), mesulergine (0.1 microM), ICS 205930 (0.1 and 1 microM), and spiroperidol (1 and 7 microM) did not affect the TFMPP-induced inhibition of the evoked ACh release. These data suggest that, in guinea pig hippocampus, the K(+)-evoked ACh release is modulated by a 5-HT1 receptor distinct from the 5-HT1A, 5-HT1B, and 5-HT1C subtypes.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Acetylcholine; Animals; Guinea Pigs; Hippocampus; Male; Piperazines; Potassium; Quinoxalines; Quipazine; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Synaptosomes; Tetrahydronaphthalenes