SCH 23390 Equivalently, but YM-09151-2 Differentially Reduces the Stimulant Effects of Methamphetamine, MK-801 and Ketamine: Assessment by Discrete Shuttle Avoidance in Mice

Abstract

ABSTRACT-The effects of intrathecal noradrenaline (NA) on the flexor reflex mediated by group II afferent fibers (group II flexor reflex) were investigated in anesthetized spinal rats. Low doses (0.01 and 0.1 pmol) of NA-HC1 inhibited the group II flexor reflex, while high doses (1 and 10 imol) facilitated it. In rats pretreated with the selective a2-antagonist yohimbine-HCI (0.1 pmol), the effect of NA-HCl (0.1 tmol) shifted from inhibition to facilitation. Intravenous administration of prazosin-HC1 (0.1 and 1 mg/kg, i.v.), a selective a,-antagonist, dose-dependently antagonized the facilitation of the group II flexor reflex induced by NA-HC1 in rats pretreated with yohimbine-HC1. The selective a,-agonist methoxamine-HC1 (1 pmol) and the a2-agonist clonidine-HC1 (0.1 tmol) facilitated and inhibited the group II flexor reflex, respectively. The effects of clonidine-HC1 and methoxamine-HC1 were almost the same as those of NA-HC1 at doses of 0.1 and 10 ,umol, respectively. NA-HCI (1 and 10 pmol) and methoxamine-HC1(1 pmol) increased the spon taneous electromyogram (EMG) spikes of the muscle tibialis anterior. The time course of the increase in the spontaneous EMG spikes was similar to that observed in the group II flexor reflex. These results suggest that NA facilitates and inhibits the group II flexor reflex via a, and a2-receptors, respectively, and one of the mechanisms of the facilitatory effects is the elevation of excitability of the a-motoneuron.Keywords: Noradrenaline, a,-Adrenoceptor, a2-Adrenoceptor, Flexor reflex, Afferent fiber (Group II)Noradrenergic neurons arising from the nucleus locus coeruleus and the subjacent subcoeruleus/medial parabrachial nuclear complex innervate both the dorsal and ventral horns of the spinal cord (1 3) and exert descending effects on the flexor reflex loop. Intrathecal or intraspinal injection of noradrenaline (NA) inhibits or facilitates the nociceptive flexor reflex (4-6). As the en hancement of the nociceptive flexor reflex induced by a agonists or L-dopa, a precursor of NA, is antagonized by a-blockers (7 12), NA is considered to exert facilitatory effects via a-receptors. Although many investigations con cerning the effects of NA on the nociceptive flexor reflex evoked by noxious stimulation which can activate group IV afferent fibers (13) have been reported, there are few reports on the effects of NA on the non-nociceptive flexor reflex. The aim of this study was to investigate the effects of intrathecal administration of NA on the flexor reflex mediated by group II afferent fibers (group II flexor re flex), which is one of the non-nociceptive flexor reflexes (14), and to elucidate the functional role of a, and a2 receptors by using antagonists and agonists. MATERIALS AND METHODSMale Wistar rats (461 ± 14 g) were anesthetized with intraperitoneal injection of urethane (400 mg/kg) and a chloralose (50 mg/kg), which were supplemented as re quired. The spinal cord was transected at the level of Th 8 9 more than 2 hr prior to recording the group II flexor reflex. The gr...

The Effects of Centrally Acting Muscle Relaxants on the Intrathecal Noradrenaline-Induced Facilitation of the Flexor Reflex Mediated by Group II Afferent Fibers in Rats

“…facilitated the group II flexor reflex remarkably in the presence of yohimbine (0.1 pmol, i.t.). The facilitation reached a peak of more than 800010 at 5 -10 min after the administration of NA, which cor responded with the previous report (14).…”

“…The group II flexor reflex is a polysynaptic reflex with more than one interneuron (15), which receives a DNTF via a,-receptors (14). In this study, the effects of CAMRs on the DNTF within the spinal cord were investigated.…”

“…catheter (PE10) was inserted through a small slit in the dura at L 1 and its tip was positioned on the left ventral aspect of the spinal cord at L2. As previ ously described (14), NA-HC1 exerts an a2-adrenoceptor mediating inhibition as well as an a,-adrenoceptor-mediat ing facilitation of the group II flexor reflex, so yohimbine HC1, a selective a2-antagonist, was given before treatment with NA-HC1 to exclude any a2-adrenoceptor-mediated effect. NA-HC1 and yohimbine-HC1 were administered via the intrathecal catheter in a volume of 10 t 1 followed by 5 it of saline.…”

“…As for CAMRs other than tizanidine and chlorpromazine, supraspinal actions (7 9), an a-blocking action (10) or relationships with cat echolamines (11,12) have been reported, but few studies have been performed concerning the effects on the DNTF. In this study, the effects of CAMRs on the DNTF within the spinal cord were studied by using the polysynaptic flexor reflex mediated by group II afferent fibers (group II flexor reflex) (13) which was facilitated by intrathecal ad ministration of noradrenaline (NA) via a,-adrenoceptors as in the previous study (14). As a first step, the effects of CAMRs on the group II flexor reflex was substantiated in an esthetized intact rats.…”

Adrenergic Receptors Modulate Motoneuron Excitability, Sensory Synaptic Transmission and Muscle Spasms After Chronic Spinal Cord Injury

“…The ␣ 2 adrenergic receptor is an ideal candidate for the regulation of the long EPSPs because ␣ 2 receptors are known to play a role in the control of afferent transmission (Clarke et al 2002;Jankowska and Hammar 2002;Rekling et al 2000). Furthermore, after SCI, inhibition over sensory transmission and reflexes can be restored by application of ␣ 2 receptor agonists (Chau et al 1998;Clarke et al 2002;Jankowska and Hammar 2002;Sakitama 1993;Tremblay and Bedard 1995). Thus another goal of this paper was to determine whether the ␣ 2 receptor inhibits the long EPSP that mediates spasms and whether loss of ligand-activated receptor activity after SCI is partly compensated for by spontaneous activity in ␣ 2 adrenergic receptors.…”