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

Abstract

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.

RX 821002 as a Tool for Physiological Investigation of α2‐Adrenoceptors

“…The idazoxan-induced increase in reflexes is inhibited by prazosin and by the 5-HT 2 receptor antagonist ICI 170809 (16,47). We believe that at least some of the reflex facilitating action of á 2 -receptor antagonists in rabbit arises from enhanced release of norepinephrine and 5-HT from the terminals of descending fibers in the ventral horn (93).…”

“…The heel-MG pathway is also enhanced by the selective 5-HT 1A receptor antagonist WAY-100635 (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)cyclohexanecarboxamide) (16), which immediately raises the question of selectivity of action of RX 821002. However, the maximal effect of the latter drug is reached with an intrathecal dose of 65 ìg (48), below the level at which it begins to block 5-HT 1A receptors in vivo (81).…”

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

“…While several investigators have examined the actions of 5-HT receptor ligands on the control of spinal cord function in vivo (e.g. Ali et al, 1994;Clarke et al, 1996;Gjerstad et al, 1996;Ogilvie et al, 1999), only a few studies have examined their actions at the spinal cellular level in vitro (e.g. Lopez-Garcia & King, 1996;Lopez-Garcia, 1998;Khasabov et al, 1999).…”

Spastic Long-Lasting Reflexes in the Awake Rat After Sacral Spinal Cord Injury

“…In contrast to the excitatory brain stem effects on motoneurons, descending brain stem inputs to the dorsal horn, especially monoaminergic, have a predominantly inhibitory affect on many afferents and interneurons, including those involved in flexor withdrawal reflexes (Baldissera et al 1981;Clarke et al 1996Clarke et al , 2002Heckman 1994;Jankowska 1992;Jankowska et al 2000;Lo et al 2003). This descending inhibition is carried largely by the ipsilateral dorsal lateral funiculus (DLF), because injuries to the DLF cause major increases in reflex transmission (i.e., release of descending inhibition), whereas injuries that spare only the DLF do not cause this release of inhibition (see excellent review in Lundberg 1982).…”