Autoradiographic mapping of 5-HT1, 5-HT1A, 5-HT1B and 5-HT2 receptors in the rat spinal cord

1 In decerebrated, non-spinalized rabbits, intrathecal administration of either of the selective 5-HTlAreceptor antagonists (S)WAY-100135 or WAY-100635 resulted in dose-dependent enhancement of the reflex responses of gastrocnemius motoneurones evoked by electrical stimulation of all myelinated afferents of the sural nerve. The approximate ED50 for WAY-100635 was 0.9 nmol and that for (S)WAY-100135 13 nmol. Intrathecal doses of the antagonists which caused maximal facilitation of reflexes in non-spinalized rabbits had no effect in spinalized preparations. 2 In non-spinalized animals, intravenous administration of (S)WAY-100135 was significantly less effective in enhancing reflexes than when it was given by the intrathecal route.3 When given intrathecally, the selective 5-HT2A/2c-receptor antagonist, ICI 170,809, produced a bellshaped dose-effect curve, augmenting reflexes at low doses (,<44 nmol), but reducing them at higher doses (982 nmol). Idazoxan, the selective 22-adrenoceptor antagonist, was less effective in enhancing reflex responses when given intrathecally after ICI 170,809 compared to when it was given alone. Intravenous ICI 170,809 resulted only in enhancement of reflexes and the facilitatory effects of subsequent intrathecal administration of idazoxan were not compromised. 4 The selective 5-HT3-receptor blocker ondansetron faciliated gastrocnemius medialis reflex responses in a dose-related manner when given by either intrathecal or intravenous routes. This drug was slightly more potent when given i.v. and it did not alter the efficacy of subsequent intrathecal administration of idazoxan. 5 None of the antagonists had any consistent effects on arterial blood pressure or heart rate. 6 These data are consistent with the idea that, in the decerebrated rabbit, 5-HT released from descending axons has multiple roles in controlling transmission through the sural-gastrocnemius medialis reflex pathway. Thus, it appears 5-HT tonically inhibits transmission between sural nerve afferents and gastrocnemius motoneurones by an action at spinal 5-HTlA-receptors. Spinal 5-HT2A/2C-receptors may mediate a weak inhibition of transmission in the spinal cord, but more convincing evidence was obtained for their involvement in descending facilitatory tone. Further, some of the facilitatory consequences of spinal a2-adrenoceptor blockade may be mediated through 5-HT2 type receptors. Spinal 5-HT3 receptors do not appear to have a major role in tonic modulation of the sural-gastrocnemius medialis reflex.

Section: -Htia-receptors and Tonic Descending Inhibitionmentioning

confidence: 80%

Spinal 5‐HT‐receptors and tonic modulation of transmission through a withdrawal reflex pathway in the decerebrated rabbit

Clarke

Harris

Houghton

1996

“…The 5-HT 1A and 5-HT 1B receptors, which are present on primary aerent terminals and dorsal horn neurons (Daval et al, 1987;Marlier et al, 1991;Ridet et al, 1994;Laporte et al, 1995) may constitute dominant receptor subtypes in the dorsal horn of the rat (see Huang & Peroutka, 1987;Marlier et al, 1991). Interestingly, Huang & Peroutka (1987) reported that at least 33% of the total 5-HT binding sites in the rat spinal cord are distinct from 5-HT 1A , 5-HT 1B or 5-HT 2C .…”

Section: Synaptic Depressionmentioning

confidence: 99%

“…Several receptors, which include the 5-HT 1 , 5-HT 2 and 5-HT 3 receptors, have been identi®ed in the spinal cord dorsal horn (e.g. Huang & Peroutka, 1987;Marlier et al, 1991;Kidd et al, 1993;Pompeiano et al, 1994). With the exception of the ionotropic 5-HT 3 receptor, all serotonergic receptors are G protein-coupled receptors and hence capable of exerting a broad modulatory in¯uence on network and cell behaviour, as most, if not all, ligand-and voltage-gated channels can be modulated by 5-HT (e.g.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological characterization of serotonin receptor subtypes modulating primary afferent input to deep dorsal horn neurons in the neonatal rat

Garraway

Hochman

2001

1 Spinal cord slices and whole-cell patch clamp recordings were used to investigate the eects of serotonergic receptor ligands on dorsal root-evoked synaptic responses in deep dorsal horn (DDH) neurons of the neonatal rat at postnatal days (P) 3 ± 6 and P10 ± 14. 2 Bath applied 5-hydroxytryptamine (5-HT) potently depressed synaptic responses in most neurons. Similarly, the 5-HT 1/7 receptor agonist, 5-carboxamidotryptamine (5-CT) depressed synaptic responses. This action was probably mediated by 5-HT 1A receptor activation, since it occurred in the presence of the 5-HT 7 receptor antagonist clozapine and was not observed in the presence of NAN-190, a 5-HT 1A receptor antagonist. In the absence of any agonist, 5-HT 1A receptor antagonists often facilitated synaptic responses, suggesting that there is sucient endogenous 5-HT to tonically activate 5-HT 1A receptors. 3 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), the 5-HT 1A/7 receptor agonist, facilitated synaptic responses, an action probably mediated by 5-HT 7 receptors, since the facilitation could be reversed by subsequent application of the 5-HT 7 receptor antagonist clozapine. 4 Agonists for the 5-HT 1B , 5-HT 2 and 5-HT 3 receptors exerted only modest modulatory actions. 5 A pharmacological analysis of the depression evoked by 5-HT suggested an action partly mediated by 5-HT 1A receptor activation, since antagonism of the 5-HT 1A receptor with NAN-190 or WAY-100635 partly reversed 5-HT-evoked depression. In comparison, 5-HT 7 receptor activation could account for much of the 5-HT-evoked facilitation. 6 We conclude that 5-HT is capable of modulating sensory input onto DDH neurons via several receptor subtypes, producing both facilitatory and depressant actions. Also, the actions of most receptor ligands on the evoked responses were similar within the ®rst 2 postnatal weeks.

“…Although Fasmer et al (1986) showed that 8-OH-DPAT 1 mg kg-' s.c. (8-hydroxy-2-(di-n-propylamino)-tetralin; a 5-HTIA receptor agonist) elicited hypoalgesia in the acute phase of the formalin test, a non-specific effect might be responsible for the weak activity of 8-OH-DPAT compared with its strong affinity to the 5-HTlA receptor (Middlemiss & Fozard, 1983). Whereas it has been demonstrated that intrathecal administration of m-CPP (selective for 5-HTlB receptors over 5-HTlA receptors, Murphy & Zemlan, 1990) induces antinociception (Eide et al, 1990;Eide, 1992), and oral administration of the drug dose-dependently inhibited both phases of the formalin-induced nociceptive response, several lines of evidence suggest that there are multiple 5-HT1 binding sites in the spinal cord, and about 35% are specific for 5-HTIB, but the density of 5-HT2 receptors is very low in the spinal cord (Leysen et al, 1982;Monroe & Smith, 1983;Marlier et al, 1991). 5-HT2 binding sites have been demonstrated in the cortex (Hoyer et al, 1986;Molineaux et al, 1989), therefore activation of spinal 5-HTlB receptors and supraspinal 5-HT2 receptors might be involved in the antinociception.…”

Section: Resultsmentioning

confidence: 99%

Meta‐chlorophenylpiperazine attenuates formalin‐induced nociceptive responses through 5‐HT_1/2 receptors in both normal and diabetic mice

Takeshita¹,

Yamaguchi²

1995

1 This study was designed to investigate the effect of meta-chlorophenylpiperazine (m-CPP; a 5-hydroxytryptamine (5-HT) receptor agonist) on the formalin-induced nociceptive responses in normal, insulin-dependent streptozotocin (STZ) diabetic and non-insulin dependent genetically diabetic (db/db) mice.2 A subcutaneous injection of diluted formalin (1% formaldehyde in 0.9% saline, 10 yl) under the plantar surface of the left hindpaw induced biphasic nociceptive responses, the first and second phases considered to represent acute and chronic pain, respectively. The former response in db/db mice was significantly lower than those in normal mice, and the latter responses in STZ and db/db mice were significantly lower than those in normal mice. 3 In normal mice, m-CPP (0.32-3.2 mg ml-', p.o.) exhibited potent antinociceptive activity, dosedependently attenuating the frst and second phase; the ID50 value of the second phase was 0.4 mg kg-'. m-CPP (0.32-3.2 mg kg-', p.o.) also dose-dependently attenuated the formalin-induced nociceptive responses in STZ-induced diabetic mice and genetically diabetic db/db mice, and the activities were comparable to those in normal mice. 4 The antinociceptive activities of m-CPP (1 mg kg-', p.o.) were significantly inhibited by pretreatment with pindolol (a 5-HTI-receptor antagonist, 1 mg kg-', i.p.) or ketanserin (a 5-HT2 receptor antagonist, 1 mg kg-', i.p.) but were hardly affected by ICS205-930 (a 5-HT3 receptor antagonist, 1 mg kg-', i.p.). 5 These results suggest that m-CPP inhibits not only acute but also chronic pain transmission through 5-HT1 and 5-HT2 receptors, and that the 5-hydroxytryptaminergic antinociceptive pathways are little affected by diabetes.