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Biomedical subjects

J Sawynok

Publications and source records attributed to J Sawynok.

At least 91 records · Page 5Linked to original sources
PubMed1985

Clonidine reverses methylxanthine-induced potentiation of baclofen antinociception.

The effect of clonidine on the antinociceptive effect of methylxanthine/baclofen and dopamine antagonist/baclofen combinations was examined to determine if alterations in noradrenaline turnover might mediate the potentiating effect of these agents. Clonidine alone had intrinsic activity in the tail flick test, so a dose and treatment schedule which produced a plateau effect was chosen. Clonidine pretreatment did not significantly alter the effect of baclofen alone, but reversed the potentiation of the action of baclofen produced by both theophylline and isobutylmethylxanthine. The intrinsic effect of isobutylmethylxanthine also was reversed. Combinations of dopamine antagonists and baclofen were potentiated or unaffected by clonidine. A possible interpretation of these results is that mutual interactions by baclofen and methylxanthines with descending noradrenergic pathways mediate the methylxanthine-induced potentiation of the antinociceptive effect of baclofen. A more specific determination of noradrenergic pathways involved in the action of baclofen will require the use of more specific alternative approaches.

1-Methyl-3-isobutylxanthine↗
PubMed1985

D-Baclofen is an antagonist at baclofen receptors mediating antinociception in the spinal cord.

The antagonistic action of D-baclofen at baclofen receptors mediating antinociception in the spinal cord was examined. Drugs were administered intrathecally to rats and effects on nociceptive threshold evaluated in the tail flick test. L-Baclofen, D-baclofen and the racemate produced dose-related increases in tail flick latency, with L-baclofen being twice as potent as the racemate and approximately 100 times more potent than D-baclofen. When D-baclofen was injected 15 min prior to L-baclofen, it produced a dose-related inhibition of the effect of L-baclofen. Concomitant administration produced a more ambiguous effect. Antagonism appeared specific for baclofen receptors because analogues with full and partial agonist activity as well as an agonist dose of D-baclofen, but not morphine or noradrenaline, were inhibited by pretreatment with D-baclofen. gamma-Aminobutyric acid (GABA) did not increase tail flick latency either alone or following pretreatment with an uptake inhibitor or a GABA-transaminase inhibitor. Antinociception produced by intrathecal administration of Baclofen appears to result from activation of a receptor which is stereoselective for the L-isomer and can be blocked by D-baclofen in doses which have initial agonist activity. This receptor may not be a GABA subtype because GABA does not mimic the effect of baclofen and the rank order of potency of analogues differs from established GABAB systems.

Alkynes↗
PubMed1984

Substance P, injected intrathecally, antagonizes the spinal antinociceptive effect of morphine, baclofen and noradrenaline.

The effect of substance P on the antinociceptive effect of morphine, baclofen and noradrenaline in the spinal cord was examined in the tail-flick and hot plate tests, after intrathecal administration. Substance P (5-20 micrograms) produced a dose-related antagonism of the effect of all three agents, which persisted for the entire time-course of the antinociceptive effect in each case. The rank order of potency of substance P and related peptides in antagonizing the antinociceptive effect of morphine, was substance P greater than physalaemin greater than eledoisin greater than eledoisin-related peptide. A similar order of potency was observed against noradrenaline, except that physalaemin appeared to be the most potent. The intrathecal administration of these peptides did not alter reaction latencies in the tail-flick test when baseline values were 2-3 sec, but produced a significant decrease in latency (hyperalgesia) when baseline values were 6-8 sec. There was a slight increase in reaction latency in the hot plate test. The specificity of the antagonism was examined by determining the effect of phentolamine on the antinociceptive effect of morphine and baclofen. Although phentolamine (30 micrograms) produced comparable hyperalgesia to substance P, it did not significantly alter the antinociceptive effect of morphine or baclofen. These results suggest that alterations in the function of substance P in the spinal cord may contribute to the spinal antinociceptive effects of morphine, baclofen and noradrenaline. The effects of substance P on nociception in the spinal cord appear to be mediated by substance P type receptors.

Afferent Pathways↗
PubMed1984

GABAergic mechanisms in antinociception.

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 GABA-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.

Alkynes↗
PubMed1984

D-Baclofen: is it an antagonist at baclofen receptors?

Following intrathecal administration into the spinal subarachnoid space, baclofen produced dose related increases in tail flick latency. L-Baclofen was twice as potent as the DL-racemate and 100 times more potent than D-baclofen. When D-baclofen was injected intrathecally 15 min prior to L-baclofen, the subsequent effect of L-baclofen was markedly reduced. This reduction was dose-related for D-baclofen in doses at least 20 times the L-baclofen dose. D-baclofen administered concomitantly with L-baclofen only slightly increased the effect of L-baclofen. Pretreatment with D-baclofen (up to 10 times the dose of L-baclofen) did not inhibit the effect of L-baclofen when drugs were injected intraperitoneally. These results indicate that D-baclofen can antagonize the antinociceptive effect of L-baclofen following intrathecal administration. D-Baclofen should prove to be a useful tool for investigation of the role of stereoselective baclofen receptors in a variety of pharmacological processes.

Analgesics↗
PubMed1984

Hyperalgesia produced by intrathecal substance P and related peptides: desensitization and cross desensitization.

The hyperalgesic effect of intrathecally administered substance P (SP), physalaemin, eledoisin and eledoisin-related peptide (ERP) was investigated in the rat tail flick test. Hyperalgesia produced by SP (2.5-15 micrograms, 1.9-11 nmol) was maximal 10-20 min after injection, lasted 30 min and was dose-related. The effect was mimicked by all of the peptides examined. The rank order of potency was physalaemin greater than SP greater than eledoisin greater than ERP. Desensitization to the hyperalgesic effect of SP was produced by three repeated intrathecal injections. Rats desensitized to SP no longer responded to physalaemin or ERP, indicating cross-desensitization. Phentolamine continued to produce hyperalgesia following such desensitization. The demonstration of a hyperalgesic effect for SP provides further support for a role for SP in nociceptive transmission. The receptor mediating this effect appears to be a SP-P subtype. Cross-desensitization between peptides suggests an action on the same receptor.

Animals↗
PubMed1983

Monoamines as mediators of the antinociceptive effect of baclofen.

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 monoamines and catecholamines (reserpine, alpha-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 alpha-MPT which increased the tail flick latency slightly. Alterations in serotonergic function did not consistently alter the action of baclofen. When baclofen was administered intrathecally, pretreatment with reserpine and alpha-MPT produced minimal alterations in antinociceptive activity. It is likely that interactions between baclofen and monoamines occur at supraspinal sites.

Analgesics↗
PubMed1983

Involvement of GABA in the antinociceptive effect of gamma-acetylenic GABA (GAG), an inhibitor of GABA-transaminase.

The role of both novel GABAB and classical GABAA receptors in GAG-induced anti-nociception was investigated using the tail flick and hot plate tests. To this end, manipulations known to increase baclofen-induced antinociception (GABAB) and the receptor antagonist bicuculline (GABAA) were used. Of the modifiers of monoamine function tested, only chlorpromazine and haloperidol significantly increased GAG-induced antinociception. Theophylline antagonized antinociception produced by both GAG and GVG. Bicuculline did not antagonize antinociception produced by either GAG or muscimol. GAG-induced antinociception does not appear to result from the activation of either classical or novel GABA receptors. An interaction with dopaminergic pathways appears to be involved.

4-Aminobutyrate Transaminase↗
PubMed1983

Theophylline-induced potentiation of the antinociceptive action of baclofen.

1--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.

Analgesics↗
PubMed1982

Lack of effect of baclofen on substance P and somatostatin release from the spinal cord in vitro.

High concentrations of K+ increase the release of substance P (SP) and somatostatin (SRIF) from superfused slices of rat spinal cord. This increase is Ca-dependent. Baclofen (100-500 microM) does not significantly alter the K+-evoked release of SP or SRIF. Stereoisomers of baclofen and GABA, similarly, are without effect. The spinal analgesic action of baclofen does not appear to be due to alterations in the release of SP or SRIF.

Animals↗
PubMed1982

On the involvement of GABA in the analgesia produced by baclofen, muscimol and morphine.

In the mouse hot-plate test (50 degrees C), 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, gamma-acetylenic GABA and gamma-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 degrees C), GABA-transaminase inhibitors produced minimal analgesia but significantly enhanced the analgesic action of baclofen. gamma-Vinyl GABA markedly increased both the peak effect and the duration of analgesia but gamma-acetylenic GABA and amino-oxyacetic acid caused smaller increases. In the mouse hot-plate test, bicuculline-sensitive GABA receptors appear to mediate the analgesic action fo muscimol. Analgesia produced by baclofen, morphine and inhibitors of GABA-transaminase may involve another class of GABA receptors which are insensitive to bicuculline.

4-Aminobutyrate Transaminase↗
PubMed1981

GABA and baclofen potentiate the K+-evoked release of methionine-enkephalin from rat striatal slices.

GABA potentiates the potassium-evoked release of methionine-enkephalin (ME) from slices of rat corpus striatum. This potentiation is observed only when a submaximal concentration (30 mM) of K+ is used to evoke release. The effect of GABA is dose-dependent between 100 and 100 micrometers. The basal release of ME is not altered by these concentrations of GABA. Before, but not muscimol, mimics the effect of GABA on the evoked release of ME. This effect is not stereoselective as both the (+)- and (-)-isomers of baclofen enhance ME release. Picrotoxin (100 micrometers) blocks the enhancement of ME release produced by both GABA and baclofen. Bicuculline methiodide (100 micrometers) does not block the effect of GABA. The effect of GABA on ME release may be mediated by an atypical GABA receptor which is activated by baclofen.

Analgesia↗
PubMed1980

Effects of morphine and naloxone on the K+-stimulated release of methionine-enkephalin from slices of rat corpus striatum.

Methionine-enkephalin (ME) released from superfused slices of rat corpus striatum was estimated by radioimmunoassay (RIA). The basal release of 2.5 +/- 0.2 pmol/g/min (0.15% of content per min) was increased approximately 3-fold upon exposure of tissue to 30 mM K+ for 5 min. This increase in release was not observed in the absence of Ca2+. Both morphine (10(-5) M) and (-)-naloxone (10(-5) and 10(-6) M) significantly depressed the release of ME evoked by 30 mM K+ did not alter basal release. The (+)-isomer of naloxone, which lacks opiate antagonist activity, did not affect basal or evoked release. A consistent depression of release was not observed when 47 mM K+ was used to evoke the release of ME. The issue of whether a feedback mechanism controls the release of ME from the striatum cannot be resolved until it is known whether the effect of morphine and naloxone on ME release are mediated by opiate or non-opiate mechanisms.

Animals↗
PubMed1979

Interactions of methylxanthines, nonxanthine phosphodiesterase inhibitors, and calcium with morphine in the guinea pig myenteric plexus.

In an earlier study, theophylline was shown to antagonize the morphine-induced inhibition of electrically induced contractions of the longitudinal muscle-myenteric plexus preparation from the guinea pig ileum. In the present study, acetylcholine (ACh) released from the myenteric plexus was measured directly using a radioenzymatic assay. Theophylline antagonized the morphine-induced inhibiton of ACh release. A similar antagonism was also observed with caffeine and 3-isobutyl-l-methylxanthine (IBMX). All three methylxanthines also increased ACh release. The nonxanthine phosphodiesterase (PDE) inhibitors 4-(3-butoxy-4-methoxy)-2-imidazolidinone (Ro 20-1724) and l-ethyl-4-isopropylidenehydrazino-1 H-pyrozolo(3,4-b)-pyridine-5-carboxylate, ethylester, HCl (SQ 20,009) generally did not antagonize the morphine-induced inhibiton of ACh release. The PDE inhibitor SQ 20,009 but not Ro 20-1724, enhanced the release of ACh. Both high calcium concentration and the divalent cation ionophore A23187 antagonized the inhibitory action of morphine on ACh release. These observations suggest that alteration in calcium fluxes rather than the inhibiton of PDE mediate the methylxanthine-induced antagonism of morphine in this preparation.

Acetylcholine↗
PubMed1978

Antagonism of morphine action on brain acetylcholine release by methylxanthines and calcium.

The inhibitory effect of morphine on the release of acetylcholine (ACh) from the rat cerebral cortex was antagonized by theophylline, caffeine and 3-isobutyl-1-methylxanthine (IBMX). Theophylline antagonism of morphine action was dose related and this agent failed to influence a comparable action of chlorpromazine on the release of ACh. Intraventricular injection of calcium also antagonized the anti-release effect of morphine. Neither methylxanthines nor calcium modified the spontaneous release of ACh in the absence of morphine. It is suggested that methylxanthine antagonism of morphine action is selective and that it could be related to the ability of methylxanthines to mobilize bound calcium.

Acetylcholine↗