cgs-12066b and 4-iodo-2-5-dimethoxyphenylisopropylamine

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

1. The decerebrate cat preparation with an intact spinal cord is characterized by a high degree of excitability in extensor motoneuron pools, which is eliminated by acute spinalization. Subtype-specific agonists for serotonin (5-HT) were investigated in terms of their effectiveness in restoring the extensor excitability following spinalization. 2. Our hypothesis was that 5-HT2 receptors have the primary role in enhancement of extensor reflex excitability, whereas 5-HT1A and 5-HT1B/D receptors are relatively unimportant. Reflex excitability was assessed from the tonic levels of force and electromyographic (EMG) output from the ankle extensors medial gastrocnemius (MG) and soleus (SOL), and from the reflex forces in both these muscles generated by ramp-and-hold stretches of MG. 3. Before spinal transection, MG and SOL usually exhibited a small amount of tonic background EMG activity and force output. Ramp-and-hold stretch of MG generated a large-amplitude reflex response. Spinal transection at the level of T10 virtually abolished tonic background activity in both extensors and greatly attenuated the MG stretch reflex. Ventral topical application of the selective 5-HT2A/2C agonist (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane hydrochloride (DOI) restored the amplitude of the MG stretch reflex in a dose-dependent fashion. However, a considerable portion of the DOI-mediated restoration of MG stretch reflex force was due to elevation of tonic background force levels above previous intact cord levels. 4. The DOI-induced increase in extensor tonic background excitability and facilitation of MG stretch reflex were reversed by ventral topical administration of the selective 5-HT2 antagonist ketanserin. No increase in extensor excitability was observed in spinalized preparations after administration of either the 5-HT1A agonist (+-)-8-hydroxy-dipropylaminotetralin hydrobromide or the 5-HT1B/1D agonist 7-trifluoromethyl-4-(4 methyl-1-piperazinyl)-pyrrolo[1,2- a]quinoxaline maleate. These data strongly suggest that the DOI-induced facilitation of extensor stretch reflex and tonic activity in spinalized preparations is mediated through an action on spinal 5-HT2 receptors. 5. One important difference between the actions of DOI in spinalized versus intact states was that the DOI-induced tonic and reflex forces in the spinalized state were subject to irregular oscillations. In contrast, DOI did not noticeably affect the smoothness of reflex force generation in the i

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Amphetamines; Animals; Cats; Decerebrate State; Electromyography; In Vitro Techniques; Quinoxalines; Reflex, Stretch; Serotonin; Serotonin Receptor Agonists

The present study examined functional supersensitivity to 5-hydroxytryptamine (5-HT) and 5-HT ligands selective for 5-HT1, 5-HT2 and 5-HT3 receptors in two tests for nociception following the spinal administration of 5,7-dihydroxytryptamine (5,7-DHT). Intrathecal pretreatment with 5,7-DHT 30-100 micrograms (following desipramine) produced a selective depletion of spinal cord 5-HT levels of > 80% and augmented the antinociceptive action of 5-HT in the tail flick and hot plate tests. The tail flick test was the more sensitive test for expression of this action. Supersensitivity was observed with the 5-HT1 receptor ligands CGS 12066B (7-trifluoromethyl-4-(4-methyl-1-piperazinyl-pyrrolo[1,2-a] quinoxalinedimaleate), RU 24969 (5-methoxy-3-(1,2,4,6-tetrahydro-4-pyridinyl)1H indole succinate), TFMPP (m-trifluoromethylphenyl-piperazine HCl), mCPP (1-(3-chlorophenyl)piperazine dihydrochloride) and 5-Me-ODMT (5-methoxy-N,N-dimethyltryptamine hydrogen oxalate) but not with the 5-HT2 receptor ligand DOI ((+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane HCl) or the 5-HT3 receptor ligand 2-Me-5-HT (2-methyl-5-hydroxytryptamine maleate) in the tail flick test. In the hot plate test, supersensitivity was observed only with 5-Me-ODMT. Intrathecal pretreatment with fluoxetine, a 5-HT uptake inhibitor, potentiated the action of 5-HT but not any of the other 5-HT1 receptor ligands examined. These results indicate that supersensitivity occurs with 5-HT and 5-HT1 receptor ligands but not with 5-HT2 or 5-HT3 receptor ligands. Both the loss of uptake sites and receptor upregulation may contribute to enhanced activity of 5-HT, but for other ligands, only the latter mechanism appears to occur.

Topics: 5,7-Dihydroxytryptamine; Amphetamines; Analgesia; Analgesics; Analysis of Variance; Animals; Binding Sites; Indoles; Injections, Spinal; Male; Pain; Piperazines; Quinoxalines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Serotonin Receptor Agonists; Up-Regulation

The present study examined the involvement of spinal noradrenergic mechanisms in spinal antinociception by the 5-hydroxy-tryptamine (5-HT) receptor-selective agonists CGS 12066B (5-HT1B; 7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo[1,2-a]quinoxaline), TFMPP (5-HT1C; M-trifluoromethylphenyl-piperazine) and DOI (5-HT2; 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) using the rat hot plate test. Effects of alpha-adrenoreceptor antagonists (phentolamine, yohimbine), the adrenergic neurotoxin 6-hydroxydopamine, and the selective noradrenergic uptake blocker desipramine were determined. CGS 12066B, TFMPP and DOI produced dose-related antinociception. The antinociceptive effect of each agent was reduced by pretreatment with both phentolamine and yohimbine (15-60 micrograms). Pretreatment with 6-hydroxydopamine (100 micrograms, intrathecal) for 7-10 days, which reduced spinal cord levels of noradrenaline by 87%, inhibited the action of TFMPP (and 5-HT), but not CGS 12066B or DOI. Pretreatment with desipramine (25 mg/kg, systemic) potentiated the action of TFMPP but not CGS 12066B or DOI (or 2-methyl-5-HT). These results suggest that antinociception by TFMPP is dependent on release of endogenous noradrenaline from the spinal cord, while that produced by CGS 12066B and DOI is not. As TFMPP exhibits a close similarity to 5-HT in these experiments, the 5-HT receptor subtype being activated to induce noradrenaline release may either be a 5-HT1C or a 5-HT1S subtype. Other mechanisms account for the observed blockade of the action of CGS 12066B and DOI by alpha-adrenoreceptor antagonists.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Adrenergic alpha-Antagonists; Amphetamines; Animals; Desipramine; In Vitro Techniques; Male; Nociceptors; Norepinephrine; Oxidopamine; Piperazines; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin; Serotonin Receptor Agonists; Spinal Cord