BACLOFEN ANALGESIA: INVOLVEMENT OF THE GABAergic SYSTEM (original) (raw)
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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
1996
This study examined the sites in the central nervous system at which subcutaneously-administered R(+)-baclofen hydrochloride (baclofen), the most active isomer of this prototypic y-aminobutyric acid (GABA) B receptor agonist, acts to produce antinociception in the rat. To determine whether baclofen acts in the spinal cord, either saline or the GABA B receptor antagonist CGP 35348 was injected intrathecally in rats pretreated 24 min earlier with 1 or 3 mg/kg s.c. baclofen. Intrathecal (i.t.) injection of 3 or 10 /~g of CGP 35348 antagonized the increase in tail-flick and hot-plate latency produced by either dose of baclofen. To determine whether baclofen acts at sites in the ventromedial medulla (VMM), either saline or CGP 35348 was microinjected in the nucleus raphe magnus or nucleus reticularis gigantocellularis pars ct of rats pretreated 24 min earlier with 1 or 3 mg/kg s.c. baclofen. Microinjection of 0.5 or 3 /~g of CGP 35348 at sites in the V1V[M produced at best only a very modest attenuation of the antinociceptive effects of baclofen. These data suggest that systemically-administered baclofen acts at sites in both the spinal cord and the VMM, but that its antinociceptive effects are likely to be mediated to a greater extent by a spinal, rather than medullary site of action. However, a definitive comparison of the relative contribution of GABA B receptors in these two regions is precluded by differences in the diffusion and concentrations of the antagonist in the spinal cord and brainstem. Finally, microinjection of 0.5 or 3.0/zg of CGP 35348 in the nucleus raphe magnus or nucleus reticularis gigantocellularis pars a of saline-pretreated rats did not alter tail-flick or hot-plate latency. This finding suggests that, unlike GABA A receptors, GABA B receptors do not mediate the tonic GABAergic input to neurons in these nuclei.
On the involvement of GABA in the analgesia produced by baclofen, muscimol and morphine
Neuropharmacology, 1982
In the mouse hot-plate test (WC), muscimol produced analgesia which was blocked by bicuculline but not by picrotoxin. Analgesia produced by baclofen was dose-dependent and stereoselective, but was not blocked by bicuculline, picrotoxin or naloxone. Morphine-induced analgesia was not altered by bicuculline. The inhibitors of GABA-transaminase, amino-oxyacetic acid, y-acetylenic GABA and y-vinyl GABA, produced analgesia which was much more prolonged than that observed with muscimol, baclofen or morphine. The analgesic action of these agents was not significantly altered by bicuculline. At a higher plate temperature (55"C), GABA-transaminase inhibitors produced minimal analgesia but significantly enhanced the analgesic action of baclofen. y-Vinyl GABA markedly increased both the peak effect and the duration of analgesia but y-acetylenic GABA and amino-oxyacetic acid caused smaller increases. In the mouse hot-plate test, bicuculhne-sensitive GABA receptors appear to mediate the analgesic action of muscimol. Analgesia produced by baclofen, morphine and inhibitors of GABA-transaminase may involve another class of GABA receptors which are insensitive to bicuculline.
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.
Systemic and intrathecal baclofen produce bladder antinociception in rats
BMC Urology
Background Baclofen, a clinically available GABAB receptor agonist, produces non-opioid analgesia in multiple models of pain but has not been tested for effects on bladder nociception. Methods A series of experiments examined the effects of systemic and spinally administered baclofen on bladder nociception in female anesthetized rats. Models of bladder nociception included those which employed neonatal and adult bladder inflammation to produce bladder hypersensitivity. Results Cumulative intraperitoneal dosing (1–8 mg/kg IP) and cumulative intrathecal dosing (10–160 ng IT) of baclofen led to dose-dependent inhibition of visceromotor responses (VMRs) to urinary bladder distension (UBD) in all tested models. There were no differences in the magnitude of the analgesic effects of baclofen as a function of inflammation versus no inflammation treatments. Hemodynamic (pressor) responses to UBD were similarly inhibited by IT baclofen as well as UBD-evoked excitatory responses of spinal dors...
Theophylline-induced potentiation of the antinociceptive action of baclofen
British Journal of Pharmacology, 1983
Theophylline (35,50 mg/kg) potentiated the antinociceptive action of intraperitoneally administered baclofen in the tail flick and hot plate tests. Potentiation was most marked when the pretreatment time was 1 h, but some potentiation was still apparent following a 2 h pretreatment. 2 Theophylline alone (50 mg/kg) produced only slight alterations in reaction latency in the two tests. 3 When baclofen was applied directly into the spinal subarachnoid space, a 1 h pretreatment with theophylline produced minimal effects, but a 2 h pretreatment produced an increase in the antinociceptive action of baclofen. 4 These results suggest that theophylline can potentiate the antinociceptive action of baclofen by actions at both supraspinal and spinal sites.
Barbiturate-induced analgesia: Permissive role of a GABAA agonist
Pharmacology Biochemistry and Behavior, 1989
PHARMACOL BIOCHEM BEHAV 32(4) 897-900, 1989.-Three doses (0.025, 0.25 and 2.5 mg) of the short-acting barbiturate, pentothal, were injected intrathecally at the lumbar level of the spinal cord of female rats and did not produce analgesia in either the tail-flick latency to radiant heat (TFL) or vocalization-threshold-to-tail-shock (VTTS) tests. However, when the high dose of pentothal (2.5 mg) was given in combination with a nonanalgesia producing dose of the GABA A agonist muscimol (1 txg), a significant and prolonged analgesia was produced in both the VTTS and TFL tests, lasting up to one hour postinjection. Intrathecal injection of the intermediate dose of pentothal (0.25 mg) in combination with 1 Ixg muscimol also produced significant analgesia in the TFL but not the VTTS test. We suggest that barbiturates may act on spinal nociceptive pathways to reduce pain thresholds only when sufficient GABAergic activity is present.
Monoamines as mediators of the antinociceptive effect of baclofen
Naunyn Schmied Arch Pharmacol, 1983
The antinociceptive activity of baclofen was evaluated in rats using the tail flick and hot plate tests. When baclofen was administered intraperitoneally, pretreatment with depletors of monamines and cateeholamines (reserpine, c~-MPT) produced a marked increase in antinociceptive activity in both tests. Blockade of noradrenergic and dopaminergic receptors with phentolamine, chlorpromazine and haloperidol produced similar increases. These agents were without intrinsic effect in these tests except for ~-MPT which increased the tail flick latency slightly. Alterations in sermonergic function did not consistently alter the action of baclofen. When baclofen was administered intrathecally, pretreatment with reserpine and ~-MPT produced minimal alterations in antinociceptive activity. It is likely that intractions between baclofen and monoamines occur at supraspinal sites.
GABA B mediated analgesia in tonic pain in monkeys
Indian journal of physiology and pharmacology, 1993
The present study was designed to characterise the analgesia produced by the GABA B agonist baclofen in tonic pain in monkeys. The effect of various doses of baclofen was studied on formalin induced pain. Baclofen was injected intraperitoneally 30 min prior to formalin injection in five doses of 2, 4, 6, 8, and 10 mg/kg and the pain was quantified for a period of one hour. Baclofen produced dose related analgesia, 6 mg/kg having maximal effect. The antinociceptive effect of baclofen could be attributed to the effect of baclofen on GABA B receptors producing presynaptic inhibition of primary nociceptive afferents in the dorsal horn of the spinal cord.