Antinociception produced by systemic R(+)-baclofen hydrochloride is attenuated by CGP 35348 administered to the spinal cord or ventromedial medulla of rats (original) (raw)
Related papers
British Journal of Pharmacology, 1989
The electrophysiological actions of the GABAB agonist, (-)-baclofen, on deep dorsal horn neurones were studied using an in vitro preparation of the spinal cord of 9-16 day old rat. 2 On all neurones tested, (-)-baclofen (100nM-30.uM) had a hyperpolarizing action which was associated with a reduction in apparent membrane input resistance. The increase in membrane conductance was dose-dependent and had a Hill coefficient of 1.0. 3 The (-)-baclofen-activated hyperpolarization persisted in the presence of bicuculline (50 gM) and Mg2+ (20mM). 4 The reversal potential of the hyperpolarizing event was estimated at 102 mV and was made less negative by increasing the external concentration of potassium ions. 5 Over the same concentration range, (-baclofen also depressed the polysynaptic composite excitatory postsynaptic potentials (e.p.s.ps) evoked in these neurones by electrical stimulation of the dorsal root entry zone. 6 The potassium channel blockers caesium, applied intracellularly, and barium, applied extracellularly, depressed the postsynaptic response to baclofen but not its effect on e.p.s.ps. 7 We propose that (-baclofen has more than one mechanism of action in spinal dorsal horn: a postsynaptic action mediated via an increase in potassium conductance and a presynaptic action that is not associated with potassium channels and may be mediated via calcium channels. Since previous studies have demonstrated little effect of (-)-baclofen on transmitter release in spinal cord, it is possible that the postsynaptic hyperpolarizing action of (-)-baclofen may account for its clinical potency as an anti-spastic agent.
BACLOFEN ANALGESIA: INVOLVEMENT OF THE GABAergic SYSTEM
Pharmacological Research, 2002
The effect of baclofen, a GABA(B) agonist, has been studied in the hot plate test in mice, to analyze the possible involvement of the GABAergic system in baclofen analgesia. Baclofen (1-3 mg kg(-1) intraperitoneal (i.p.)) was found to elicit a dose-dependent antinociceptive effect. The antinociceptive effect of baclofen cannot be due to motor incoordination or sedation as the doses of baclofen which produce analgesia did not induce these effects during the rota-rod test. The antinociceptive effect of baclofen was reversed by 2-hydroxysaclofen, a GABA(B) antagonist by both systemic (3 mg kg(-1)) and intra cisterna magna (intracisternal (i.c.)) (0.3 mg kg(-1)) administration. The antagonist dose administered via i.c. produced a complete blockade and was 10-fold lower than the dose employed in i.p. administration. The data suggest that the antinociceptive effect of baclofen is GABA(B) receptor-mediated and reveal a central location of the analgesic effect of baclofen.
Pharmacology Biochemistry and Behavior, 1999
ADVOKAT, C., M. DUKE AND R. ZERINGUE. Dissociation of ( Ϫ )baclofen-induced effects on the tail withdrawal and hindlimb flexor reflexes of chronic spinal rats . PHARMACOL BIOCHEM BEHAV 63 (4) 527-534, 1999.-We previously reported that the antinociceptive effect of the GABA B receptor agonist, ( Ϫ )baclofen, in chronic spinal rats depended on the route of administration. That is, subcutaneous (SC) injections significantly increased the latency of the thermally elicited tail withdrawal (tail flick, TF) reflex, whereas spinal (intrathecal, IT) injections did not. The present studies attempted to determine the reason for this differential response. The possible contribution of a peripheral component to the systemic effect was evaluated, but was not supported by negative results of intradermal ( Ϫ )baclofen injections (50 and 500 g) into the tail skin of chronic spinal rats. A spinal site of action was indicated when pretreatment with 30 g, IT of the GABA B receptor antagonist, phaclofen, significantly reduced the antinociceptive effect of SC ( Ϫ )baclofen in both chronic spinal (5 mg/kg) and intact rats (2 mg/kg). Moreover, direct IT injections of ( Ϫ )baclofen in chronic spinal rats produced a modest, but statistically significant increase in TF latency at doses of 0.06, 0.12, 0.3, and 0.6 g, but not 1.2 g. In the same spinal preparation, the flexor response was significantly reduced by IT injection of 0.6 and 1.2 g, but not lower doses of 0.3 and 0.12 g. These results provide the first quantitative, electrophysiological evidence of an antispastic effect of IT ( Ϫ )baclofen in an in vivo, unanesthetized animal model. Second, the data show a separation between an antinociceptive effect of low spinal doses and an antispastic/muscle relaxant effect at higher doses, which may account for the results of our prior report. Finally, the data are also consistent with behavioral reports of antiallodynic/analgesic effects of low-dose baclofen, and may be relevant to the electrophysiological evidence of a preferential presynaptic action of low-dose ( Ϫ )baclofen at the primary afferent synapse.
Actions of (−)-baclofen on rat dorsal horn neurons
Brain Research, 1991
The actions of a y-aminobutyric acid B (GABAB) agonist, (-)-baclofen, on the electrophysiological properties of neurons and synaptic transmission in the spinal dorsal horn (laminae l-IV) were examined by using intraceUular recordings in spinal cord slice from young rats. in addition, the effects of baclofen on the dorsal root stimulation-evoked outflow of glutamate and aspartate from the spinal dorsal horn were examined by using high performance liquid chromatography (HPLC) with flourimetric detection. Superfusion of baclofen (5 nM to l0 ~M) hyperpolarized, in a stereoselective and bicuculline-insensitive manner, the majority (86%) of tested neurons. The hyperpolarization was associated with a decrease in membrane resistance and persisted in a nominally zero-Ca 2+, 10 mM Mg 2+-or a TI'X-containing solution. Our findings indicate that the hyperpolarizing effect of baclofen is probably due to an increase in conductance to potassium ions, Baclofen decreased the direct excitability of dorsal horn neurons, enhanced accommodation of spike discharge, and reduced the duration of Ca 2+-dependent action potentials. Baclofen depressed, or blocked, excitatory postsynaptic potentials evoked by electrical stimulation of the dorsal roots. Spontaneously occurring synaptic potentials were also reversibly depressed by baclofen. Whereas baclofen did not produce any consistent change in the rate of the basal outflow of glutamate and aspartate, the stimulation-evoked release of the amino acids was blocked. The present results suggest that baclofen, by activating GABA~ receptors, may modulate spinal afferent processing in the superficial dorsal horn by at least two mechanisms: (1) baclofen depresses excitatory synaptic transmission primarily by a presynaptic mechanism involving a decrease in the release of excitatory amino acids, and (2) at higher concentrations, the hyperpolarization and increased membrane conductance may contribute to the depressant effect of baclofen on excitatory synaptic transmission in the rat spinal dorsal horn.
Baclofen antagonism by 2-hydroxy-saclofen in the cat spinal cord
Neuroscience Letters, 1988
When administered microelectrophoretically, a sulphonic acid derivative of baclofen, 3-amino-2-(4chlorophenyl)-2-hydroxy-propylsulphonic acid, reversibly reduced the presynaptic reduction by (-)-baclofen of the monosynaptic excitation of spinal interneurones by impulses in low threshold primary afferent fibres of the cat as well as the postsynaptic depression by (-)-baciofen of the firing of these neurones. This compound, 2-hydroxy-saclofen, may be useful in assessing the physiological significance of central baclofen receptors.
Gabaergic mechanisms in antinociception
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 1984
GABAergic mechanisms appear to be involved in antinociceptive processes. Generally, peripheral administration of GABAergic agents increases the antinociceptive effect of morphine, but central administration inhibits this effect, suggesting that multiple interactions may occur. GABAergic agents also can produce antinociception directly. Muscimol and THIP (GABAA agonists) act at supraspinal sites to produce antinociception, but do not appear to interact with bicuculline sensitive receptors. Baclofen (a GABAB agonist) acts at both supraspinal and spinal sites. Supraspinal mechanisms include inhibition of ascending noradrenergic and dopaminergic pathways but activation of descending noradrenergic pathways. The spinal mechanism may involve postsynaptic inhibition of the effect of substance P. D-Baclofen is an antagonist at spinal baclofen receptors. Antinociception produced by inhibitors of GABA-transaminase is not reduced by bicuculline in most studies, while manipulations which increase the antinociceptive effect of baclofen do not alter or block the effect of GA&A-transaminase inhibitors. An understanding of the role of GABAA and GABAB receptors in antinociception will require clarification of some curious pharmacological actions of bicuculline and the use of a specific GABAB receptor antagonist.
Neuroscience Letters, 2004
An in vitro mouse hemisected spinal cord was used to characterize the g-aminobutyric acid receptor type B (GABA B ) modulation of the ventral root potential (VRP) in response to electrical stimulation of the dorsal root (DR). Low-intensity (LI) and high-intensity (HI) stimulation induced VRPs with progressively higher amplitude and duration. Repetitive HI-stimulation of the DR (1 -10 Hz) produced windup. The selective GABA B receptor agonist, CGP35024, inhibited the VRPs in a dose-dependent manner. The inhibitory action of CGP35024 was blocked by CGP52432, a potent GABA B receptor antagonist. Following washout of the GABA B receptor agonist, VRPs and windup were significantly enhanced. The rebound increase of the VRP following removal of CGP35024 was also blocked by the GABA B receptor antagonist, CGP52432. This phenomenon is not linked to receptor desensitization, but rather due to GABA B receptor-induced hyperactivity of N-, P/Q-type Ca 2þ channels, as v-CgTx GVIA and MVIIC abolished/prevented the increase. The 'rebound' enhancement of the spinal transmission after exposure to GABA B agonists sheds light on the possible mechanism of the severe withdrawal effects after abrupt termination of baclofen treatment in patients suffering from multiple sclerosis. q
GABAergic mechanisms of analgesia: An update
Pharmacology Biochemistry and Behavior, 1987
1987.-Both directly acting (GABAA and GABAa agonists) and indirectly acting GABAergic agents (GABA uptake inhibitors and GABA-transaminase inhibitors) produce analgesia in a variety of animal test systems. Analgesia produced by GABAA agonists is probably due to a supraspinal action, although spinal sites may also play a role. GABAA agonist analgesia is insensitive to naloxone, bicuculline, picrotoxin and haloperidol, but is blocked by atropine, scopolamine and yohimbine suggesting a critical role for central cholinergic and noradrenergic pathways in this action. The lack of blockade by the GABAA antagonist bicuculline is difficult to explain. Both bicucuUine and picrotoxin have intrinsic analgesia actions which may not necessarily be mediated by GABA receptors. The GABAB agonist baclofen produces analgesia by actions at both spinal and supraspinal sites. Baclofen analgesia is insensitive to naloxone, bicuculline and picrotoxin, and blockade by chlorinergic antagonists occurs only under limited conditions. Catecholamines are important mediators of baclofen analgesia because analgesia is potentiated by reserpine, t~-methyl-p-tyrosine, phentolamine, ergotamine, haloperidol and chlorpromazine. A role for serotonergic mechanisms is less well defined. Methylxanthines, which produce a clonidinesensitive increase in noradrenaline (NA) turnover, increase baclofen analgesia by a clonidine-sensitive mechanism. Both ascending and descending NA pathways are implicated in the action of baciofen because dorsal bundle lesions, intrathecal 6-hydroxydopamine and medullary A1 lesions markedly decrease baclofen analgesia. However, simultaneous depletion of NA in ascending and descending pathways by locus coeruleus lesions potentiates baclofen analgesia suggesting a functionally important interaction between the two aspects. Baclofen analgesia within the spinal cord may be mediated by a distinct baclofen receptor because GABA does not mimic the effect of baclofen and the rank order of potency both of close structural analogs of baclofen as well as antagonists differs for analgesia and GABAB systems. The spinal mechanism may involve an interaction with substance P (SP) because SP blocks baclofen analgesia, and desensitization to SP alters the spinal analgesic effect of baciofen. GABA uptake inhibitors produce analgesia which is similar to that produced by GABAA agonists because it is blocked by atropine, scopolamine and yohimbine. Analgesia produced by GABA-transaminase inhibitors is similar to that produced by GABAA agonists because it can be blocked by atropine, but it is potentiated by haloperidol while THIP analgesia is not. Analgesia by GABA-transaminase inhibitors also is similar to baclofen analgesia in that it is increased by haloperidol and chlorpromazine, but it is inhibited by theophylline while baclofen analgesia is potentiated. The possibility that indirectly acting GABAergic agents can produce analgesia by mechanisms unrelated to GABA should be considered. Analgesia THIP Muscimol Baclofen Noradrenergic pathways Baclofen antagonists
Brain Research, 2006
The ventrobasal complex of the thalamus (VB) participates in the transmission and modulation of noxious information. Recent data suggested that GABA(B) receptors in the VB might be involved in the modulation of neuronal activity in response to chronic noxious input. However, in acute inflammatory pain, the role of GABA(B) receptors in the VB remains unknown. The formalin test of nociception was performed in rats stereotaxically injected in the VB contralateral to the formalin-injected paw, with saline (controls), baclofen (0.5 and 0.875 microg), a specific GABA(B) receptor agonist or CGP35348 (25 microg), a GABA(B) receptor antagonist. Control animals exhibited phase 1 (acute pain) and phase 2 (tonic pain) nociception-related activities as previously described. The higher dose of baclofen induced a significant decrease of all pain-related behaviors in both phases of the test and had no observable effects on the animals' motor function, while the lower dose could not reduce the total pain-related activities. Injection of CGP35348 prior to baclofen reduced the antinociceptive effect caused by baclofen during phase 2 in the paw-jerks and in total pain-related activities. CGP35348 alone had antinociceptive effects in both phases, though less pronounced than baclofen 0.875 microg in the total pain-related activities during phase 2. Data demonstrate that both the blockade and the activation of GABA(B) receptors in the VB of rats induce antinociception in acute and tonic pain. An important role for GABA(B) receptors on the thalamic processing of nociceptive input in the VB is suggested.
Brain Research, 1993
This study examined whether the antinociception produced by glutaminergic stimulation of neurons in the nucleus raphe magnus (NRM) and nucleus reticularis gigantocellularis pars (Y (NGCpal is mediated by an action of GABA at GABA, receptors in the spinal cord. Rats were pretreated with intrathecal (i.t.1 administration of the selective GABA, receptor antagonists phaclofen (100 kg) or CGP 35348 (30 rg), the serotonin receptor antagonist methysergide (30 pgl, or vehicle. Fifteen min later, 30 nmol L-glutamate was microinjected into the NRM, NGCpcq or sites in the medulla outside these two regions. Microinjection of L-glutamate into the NRM or NGCpo in vehicle-pretreated rats significantly increased tail flick latency. This increase was antagonized, but not abolished, by i.t pretreatment with 30 Fg CGP 35348 or 100 pg phaclofen. Pretreatment with 30 pg methysergide completely antagonized the antinociception produced by L-glutamate. Microinjection of L-glutamate at medullary sites outside the NRM or NGCpa did not produce antinociception. In an ancillary experiment, the possibility that the ability of methysergide, phaclofen or CGP 35348 to antagonize glutamate-induced antinociception was related to non-specific increases in tail skin temperature was explored. Although phaclofen or methysergide increased tail skin temperature, the magnitude and time course of this increase were not consistent with the antagonism of glutamate-induced antinociception. Moreover, administration of CGP 35348 resulted in a modest decrease in tail skin temperature. Thus, antagonism of glutamate-induced antinociception does not appear to result from non-specific alterations in tail skin temperature. Taken together, these results indicate that the antinociception produced by activation of neurons in the NRM and NGCpa is at least partially mediated by GABA, receptors in the spinal cord.