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J Sawynok

Publications and source records attributed to J Sawynok.

At least 73 records · Page 4Linked to original sources
PubMed1988

Role of G-proteins and adenylate cyclase in antinociception produced by intrathecal purines.

The effects of pertussis toxin, forskolin and phosphodiesterase inhibitors on the antinociceptive action of intrathecal purines were examined to investigate the possible involvement of adenylate cyclase in spinal antinociception. Pretreatment with pertussis toxin (0.25 and 0.5 microgram) inhibited the antinociceptive action of L-phenyl-isopropyladenosine (L-PIA), N6-cyclohexyladenosine (CHA) and 5'-N-ethylcarboxamide adenosine (NECA) in the tail flick and hot plate tests. Forskolin (10-30 micrograms) reduced the effect of CHA and NECA in the hot plate test. Ro 201724 (30 micrograms) and Rolipram (20 micrograms) inhibited CHA in the tail flick and hot plate tests, but did not affect NECA in either test. These results suggest (1) spinal antinociception by purines is mediated by interactions with G-proteins (Gi linked to adenylate cyclase and/or Go linked to ion channels) (2) spinal antinociception by CHA is due to inhibition of adenylate cyclase (3) a separate mechanism, which does not involve stimulation of adenylate cyclase, may be involved in the spinal action of NECA.

Adenylate Cyclase Toxin↗
PubMed1988

5-Hydroxytryptamine releases adenosine from primary afferent nerve terminals in the spinal cord.

5-Hydroxytryptamine (serotonin, 5-HT) increased the release of endogenous adenosine from dorsal, but not ventral, spinal cord synaptosomes. This release was reduced by (i) the 5-HT receptor antagonist methysergide, (ii) removal of Ca2+ from the medium, (iii) inhibition of ecto-5'-nucleotidase and (iv) capsaicin pretreatment. These data suggest that activation of 5-HT receptors on primary afferent terminals releases a nucleotide which is converted extracellularly to adenosine. This adenosine may contribute to the spinal antinociceptive effect of 5-HT.

Adenosine↗
PubMed1988

Pertussis toxin inhibits antinociception produced by intrathecal injection of morphine, noradrenaline and baclofen.

The effect of intrathecal pretreatment with pertussis toxin on the spinal antinociceptive effect of morphine, noradrenaline and L-baclofen was examined in rats implanted with chronic indwelling cannulas. Pretreatment with 0.25-0.75 micrograms pertussis toxin for 2-7 days inhibited antinociception produced by intrathecal injection of all three agents in the tail flick test. Inhibition also occurred in the hot plate test, but was less pronounced than in the tail flick test. When doses of the three agents giving similar levels of antinociception were compared in a single group, the degree of inhibition of antinociception was comparable. Inhibition of the effect of noradrenaline was observed up to 14 days following pretreatment. The sensitivity of spinal antinociception to pertussis toxin suggests involvement of a guanine nucleotide regulatory protein in spinal actions of morphine, noradrenaline and L-baclofen. There is support in the literature for the additional involvement of adenylate cyclase in the action of morphine and noradrenaline but not of baclofen.

Adenylate Cyclase Toxin↗
PubMed1988

Role of ascending and descending serotonergic pathways in the antinociceptive effect of baclofen.

The role of ascending and descending serotonergic pathways in the antinociceptive effect of baclofen was examined by lesioning specific pathways with the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). Antinociception in rats was assessed using the tail flick and hot plate tests 3/4 and 10/11 days after lesioning and the placement of lesions verified by analysis of serotonin (5-HT) in brain and spinal cord. Lesions to the ventromedial tegmentum depleted 5-HT selectively in brain and inhibited the antinociceptive effect of baclofen in the tail flick test 3/4 but not 10/11 days after lesioning. Lesions to the nucleus raphe medianus produced a marked depletion of 5-HT in the hippocampus and produced the same effect on baclofen. Lesions to the nucleus raphe dorsalis were less selective, depleting 5-HT in a number of brain regions and in the spinal cord, and inhibited the antinociceptive effect of baclofen at the later but not the earlier time interval. Lesions to descending pathways by microinjection of 5,7-DHT into the ventral raphe or nucleus raphe magnus did not affect the action of baclofen significantly. Lesions to both ascending and descending pathways by intracerebroventricular 5,7-DHT increased the effect of baclofen. The hot plate test generally was less sensitive to these manipulations, although changes parallel to the tail flick test were observed in a number of instances. Both the destruction of 5-HT pathways and development of supersensitivity at 5-HT receptors may contribute to the interactions observed.

5,7-Dihydroxytryptamine↗
PubMed1987

Effect of 6-hydroxydopamine-induced lesions to ascending and descending noradrenergic pathways on morphine analgesia.

A systematic study of the role of descending, ascending and both aspects of noradrenergic pathways in the analgesic action of morphine was undertaken. The neurotoxin 6-hydroxydopamine (6-OHDA) was microinjected into the medullary A1 region, the dorsal bundle (DB), locus coeruleus (LC) or the cerebral ventricles (i.c.v.) to deplete noradrenaline (NA) in these pathways. The analgesic effect of systemically administered morphine 7-15 mg/kg was generally tested 7-12 days postlesion, and at the end of the experiment, brain and spinal cord regions were extracted and NA and dopamine (DA) measured by HPLC to verify the placement of lesions. Medullary A1 lesions profoundly depleted spinal cord NA with only a modest effect on mesencephalic levels. Such lesions inhibited the effect of morphine in a pressure test, but not in thermal tests (tail flick and hot plate) for nociception. DB lesions reduced NA in the cortex, hippocampus, hypothalamus and midbrain, but not in the spinal cord, and potentiated morphine analgesia in thermal tests for nociception. DA levels in the striatum were normal in this group. In another group where different stereotaxic coordinates were used, the pattern of NA depletion was similar, but DA levels in the striatum were reduced. In this group, potentiation of analgesia was no longer observed. LC lesions depleted NA throughout the neuraxis and potentiated morphine analgesia in both pressure and thermal tests for nociception. I.c.v. 6-OHDA depleted NA to a comparable degree to LC lesions, but striatal DA levels also were reduced and potentiation of morphine analgesia was not observed. These results indicate that central NA pathways are critical to the expression of morphine analgesia. The effect of depletion of NA in both ascending and descending aspects is the same as depletion in ascending pathways only, suggesting that this pathway is an important mediator of morphine analgesia. Simultaneous depletion of DA in the striatum can reverse the potentiating action of NA depletion indicating a critical role for DA with respect to NA pathways and mechanisms of analgesia.

Analgesia↗
PubMed1987

Enhancement of clonidine-induced analgesia by lesions induced with spinal and intracerebroventricular administration of 5,7-dihydroxytryptamine.

The role of serotonin (5-HT) in analgesia induced by clonidine was examined by determining the effect of intraspinal (i.s.) and intracerebroventricular (i.c.v.) injections of 5,7-dihydroxytryptamine (5,7-DHT) on analgesia produced by clonidine in the tail-flick and hot plate tests. Depletion of amines was verified by high performance liquid chromatography analysis. Intraspinal injections of 5,7-DHT potentiated the action of clonidine in both tests for analgesia and caused depletion of 5-HT in the spinal cord. Intracerebroventricularly injected 5,7-DHT also increased the action of clonidine and depleted 5-HT in brain as well as in the spinal cord. In the groups given intracerebroventricular injections, there appeared to be a biphasic increase in the action of the clonidine. Significant hyperalgesia from pretreatment with neurotoxin was observed only on a limited number of occasions. The present results indicate that 5-HT mechanisms in the CNS are important mediators of the analgesic action of clonidine. Interactions between clonidine and 5-HT systems at both spinal and supraspinal sites are considered.

5,7-Dihydroxytryptamine↗
PubMed1987

GABAergic mechanisms of analgesia: an update.

Both directly acting (GABAA and GABAB 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 bicuculline 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 cholinergic antagonists occurs only under limited conditions. Catecholamines are important mediators of baclofen analgesia because analgesia is potentiated by reserpine, alpha-methyl-p-tyrosine, phentolamine, ergotamine, haloperidol and chlorpromazine. A role for serotonergic mechanisms is less well defined. Methylxanthines, which produce a clonidine-sensitive 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 baclofen 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 baclofen. 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.(ABSTRACT TRUNCATED AT 400 WORDS)

Analgesia↗
PubMed1987

Substance P-induced long-term blockade of spinal adrenergic analgesia: reversal by morphine and naloxone.

Alpha agonists [noradrenaline (NA) and ST-91] inhibit the release of substance P (SP) from the spinal cord and block the biting, licking, scratching syndrome produced by intrathecal SP suggesting that these agents produce analgesia by an interaction with SP systems. In this study we determined the effect of a desensitizing regimen of SP (15 micrograms X 2 at a 30-min interval) on analgesia produced by intrathecal NA in the rat tail-flick test. When NA was injected immediately after the regimen or after a 90-minute delay, NA analgesia was blocked. This blockade persisted up to 11 days after exposure to SP. Exposure to a single dose of SP (15 or 30 micrograms) also blocked NA acutely, but the long-term blockade did not last as long. An identical effect was observed with ST-91. SP (15 micrograms X 2) potentiated the analgesic action of morphine acutely, but no interaction was observed 4 to 7 days later. Pretreatment with morphine and naloxone prevented the long-term blockade by SP. The effect of naloxone was not reversed by naltrexone suggesting that occupation of opiate receptors rather than an apparent agonist effect of naloxone caused the protection. Pretreatment with clonidine had only a slight effect on long-term blockade, but yohimbine was without effect. The present study describes a new long-term interaction between SP and alpha-2 agonists in the spinal cord. The mechanism(s) of the observed blockade by SP remains to be elucidated. However, there appears to be a functionally significant interaction between opiate and alpha-2 receptors in the spinal cord.

Analgesia↗
PubMed1987

Involvement of adenosine in the spinal antinociceptive effects of morphine and noradrenaline.

Intrathecal (i.t.) pretreatment of rats with either theophylline (50 micrograms) or 8-phenyltheophylline (3 micrograms) antagonized antinociception produced by i.t. injection of morphine (0.3-3 micrograms) in the tailflick and hotplate tests, but had no effect on antinociception produced by i.t. injection of noradrenaline (10-30 micrograms). In other experiments designed to test whether morphine released adenosine from the spinal cord, adenosine release from synaptosomes was measured by high-performance liquid chromatography with fluorescence detection of etheno-adenosine. Depolarization with 24 mM K+ or 50 microM veratridine released 3 times as much adenosine from dorsal than from ventral spinal cord synaptosomes. K+ released primarily adenosine whereas veratridine released both adenosine and nucleotide(s). Morphine (1-100 microM) produced a Ca++-dependent release of endogenous adenosine, comparable to K+-evoked adenosine release, which was blocked by 1 microM naltrexone. Noradrenaline (5-500 microM) produced a Ca++-dependent release of a nucleotide which was subsequently degraded extracellularly to adenosine by ecto-5'-nucleotidase. This release was antagonized by 10 microM phentolamine and by 1 microM yohimbine. These results suggest that, within the spinal cord, morphine may act on opioid receptors to release adenosine which subsequently acts at adenosine receptors to produce spinal analgesia. Spinal analgesia produced by noradrenaline does not appear to involve adenosine release.

Adenosine↗
PubMed1986

Role of ascending and descending noradrenergic pathways in the antinociceptive effect of baclofen and clonidine.

Baclofen and clonidine interact with central noradrenaline (NA) pathways by a variety of mechanisms. The specific role of ascending and descending pathways in antinociception produced by these agents was examined by lesioning the dorsal bundle (DB), locus coeruleus (LC) and descending NA pathways by the microinjection of the neurotoxin 6-hydroxydopamine (6-OHDA). Lesions were verified using high-performance liquid chromatography analysis of NA. Both baclofen and clonidine were injected intraperitoneally in all experiments. The antinociceptive effect of baclofen in the tail-flick test was inhibited 7-21 days after DB lesions. This manipulation decreased NA levels in cortex, hippocampus and hypothalamus but did not alter spinal cord levels. Lesions of the LC potentiated the effect of baclofen 12-16 days postlesion. NA levels were reduced in all the regions just mentioned. DB lesions produced a transient decrease in the effect of clonidine, being observed 7 but not 12-16 days postlesion. Neither acute depletion of NA levels with alpha-methyl-p-tyrosine (alpha-MPT), nor LC lesions significantly affected antinociception produced by clonidine. Intraspinal 6-OHDA potentiated the antinociceptive action of clonidine in the tail-flick test. This treatment markedly reduced spinal cord NA levels, but had minimal effects on brain NA. The results of this and previous studies in this laboratory suggest that the antinociceptive effect of baclofen is mediated by interactions with both ascending and descending NA pathways. These pathways appear to interact in a complex manner. Interpretation of data for clonidine is complicated because lesions can both deplete endogenous NA as well as inducing postsynaptic supersensitivity of alpha 2-receptors. Clonidine does not depend on endogenous NA pathways for producing antinociception because acute depletion of NA with alpha-MPT does not alter its action. Spinal sites of action are of importance following systemic clonidine because intraspinal 6-OHDA produces supersensitivity. Altering NA activity in ascending pathways alone produces a transient inhibition of the effect of clonidine, but supersensitivity is not apparent. Simultaneous lesions of both ascending and descending pathways do not produce supersensitivity, again suggesting important interactions between such pathways can occur.

Afferent Pathways↗
PubMed1986

Clonidine reverses baclofen-induced increases in noradrenaline turnover in rat brain.

The effect of baclofen and clonidine, both individually and in combination, on noradrenaline turnover was examined in several brain regions as well as in the spinal cord using the alpha-methyl-p-tyrosine depletion method. Baclofen (30-50 mg/kg) consistently increased the turnover of noradrenaline in the cortex, hippocampus and spinal cord and this effect was stereoselective for the L-isomer. Clonidine (0.1 mg/kg) decreased noradrenaline turnover in these regions and reversed the effect of baclofen. In the striatum, baclofen (50 mg/kg) decreased the turnover of dopamine in a stereoselective manner. Clonidine (0.1 mg/kg) did not alter dopamine turnover but potentiated the effect of baclofen. These results support behavioural data which suggests that baclofen interacts with central noradrenergic pathways. The nature of such interactions appears to be complex.

Animals↗
PubMed1986

Baclofen activates two distinct receptors in the rat spinal cord and guinea pig ileum.

Following intrathecal injection, pretreatment with both D-baclofen and 5-aminovaleric acid (5-AV) inhibited the antinociceptive effect of L-baclofen, but homotaurine (3-aminopropane sulphonic acid, APS) was inactive as an antagonist (rank order D-baclofen greater than 5-AV greater than APS = 0). In an established GABAB system, the electrically stimulated guinea pig longitudinal muscle myenteric plexus preparation, APS and 5-AV but not D-baclofen reduced the inhibitory effect of L-baclofen (APS = 5-AV greater than D-baclofen = 0). Receptors with which baclofen interacts in the spinal cord to produce antinociception differ from GABAB receptors with respect to the rank order of potency of antagonists as well as close structural analogs, and these criteria could be used for characterization of such receptors.

Amino Acids↗
PubMed1986

Classification of adenosine receptors mediating antinociception in the rat spinal cord.

Analogues of adenosine were injected intrathecally into rats implanted with chronic indwelling cannulae in order to determine a rank order of potency and hence characterize adenosine receptors involved in spinal antinociception. In the tail flick test L-N6-phenylisopropyl adenosine (L-PIA), cyclohexyladenosine (CHA) and 5'-N-ethylcarboxamide adenosine (NECA) produced dose-related antinociception which attained a plateau level. NECA and CHA also produced an additional distinct second phase of antinociception. D-N6-Phenylisopropyl adenosine (D-PIA) and 2-chloroadenosine (CADO) had very little antinociceptive activity in this test. The rank order of potency in producing the plateau effect was L-PIA greater than CHA greater than NECA greater than D-PIA = CADO, while that for the second phase of antinociception was NECA greater than-CHA. Pretreatment with both theophylline and 8-phenyltheophylline (8-PT) antagonized antinociception produced by CHA, with 8-PT being at least an order of magnitude more potent than theophylline. Both antagonists produced a significant hyperalgesia in the tail flick test. L-PIA and CHA also produced methylxanthine-sensitive antinociception in the hot plate test. These results suggest that activation of A1-receptors in the spinal cord can produce antinociception. Activation of A2-receptors may produce an additional effect, but the relative activity of CHA in this component of activity is unusual.

2-Chloroadenosine↗
PubMed1986

The therapeutic use of heroin: a review of the pharmacological literature.

Heroin is currently being advocated by some as a superior therapeutic agent for use in terminal illness. However, a review of the literature on heroin presently available does not support this contention. Administered orally, heroin is approximately 1.5 times more potent than morphine in controlling chronic pain in terminal cancer patients. Its effects on mood and the incidence and nature of side effects do not differ from those of morphine except in males where poorer pain control probably accounts for the worse effect on mood. Given parenterally for acute pain, heroin is 2-4 times more potent than morphine and faster in onset of action. When the potency difference is accounted for, the pharmacological effects of heroin do not differ appreciably from those of morphine. Heroin is metabolized to 6-acetylmorphine and morphine. After oral administration of heroin, morphine but not heroin or 6-acetylmorphine is detected in blood. In this case, heroin is a prodrug for the delivery of systemic morphine. Following acute i.v. administration, heroin appears transiently in blood with a half-life of about 3 min. The half-life of heroin exposed to blood or serum in vitro is 9-22 min, indicating that organ metabolism is involved in blood clearance as well. Direct renal clearance of heroin is less than 1% of the administered dose. In animal studies, heroin and 6-acetylmorphine are both more potent and faster acting than morphine as analgesics, effects attributed to their greater lipid solubility and subsequent penetration of the blood-brain barrier. Given centrally, morphine is more potent than heroin and 6-acetylmorphine in producing analgesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗
PubMed1986

Evidence that substance P may be a modulator rather than a transmitter of noxious mechanical stimulation.

Substance P (SP), injected intrathecally, produced a dose-related increase in responsiveness (hyperalgesia) in a pressure test for nociceptive thresholds. Pretreatment with two doses of SP produced complete desensitization to this response but did not alter base-line responsiveness. The hyperalgesic response to SP and the lack of change in base line following desensitization to SP suggest a modulator rather than a transmitter role for SP in the transmission of noxious mechanical stimulation.

Animals↗
PubMed1985

Evidence for the involvement of descending noradrenergic pathways in the antinociceptive effect of baclofen.

The role of descending monoaminergic pathways in the antinociceptive effect of baclofen following intraperitoneal (i.p.) administration was investigated by determining the effect of intrathecal (i.t.) administration of neurotoxins [6-hydroxydopamine (6-OHDA) and 5,6-dihydroxytryptamine (5,6-DHT)] and receptor antagonists (phentolamine and methysergide) on baclofen in the tail-flick and hot-plate tests. Pretreatment with 6-OHDA (20 and 50 micrograms) inhibited baclofen antinociception in both tests 4-13 days after treatment. but pretreatment with 5,6-DHT (20 and 100 micrograms) produced a slight increase in the tail-flick test. The higher doses of both neurotoxins produced hyperalgesia in the tail-flick test. In other experiments, baclofen was injected intraperitoneally followed by i.t. amine antagonists when a plateau level of antinociception was attained. Phentolamine (30-100 micrograms) reversed baclofen antinociception in both the tail-flick and hot-plate tests. Methysergide (30-100 micrograms) only reversed the effect of baclofen in doses greater than or equal to 50 micrograms in the tail-flick test. Phentolamine (15 and 30 micrograms) and methysergide (50 micrograms) antagonized the antinociceptive effect of i.t. noradrenaline. Both phentolamine and methysergide produced hyperalgesia in the tail-flick test. However, hyperalgesia per se does not appear to be the only factor responsible for the reversal of baclofen antinociception because dose and agent dissociations between these effects were observed. These results suggest that a major mechanism of action of baclofen in producing antinociception is the activation of noradrenergic pathways descending to the spinal cord.

5,6-Dihydroxytryptamine↗
PubMed1985

Desensitization to substance P following intrathecal injection. A technique for investigating the role of substance P in nociception.

The intrathecal injection of substance P (SP) (2.5-15 micrograms) has been shown to produce hyperalgesia in the rat tail flick test. Repeated injection of SP (7.5 or 15 micrograms) or pretreatment with two of these doses produces desensitization to this hyperalgesic response. Desensitization is dose-related with respect to degree and duration. This phenomenon is relatively specific because the hyperalgesic response to methysergide, a serotonin receptor antagonist, is unaffected, while that produced by phentolamine, an adrenergic receptor antagonist, is much less affected than that of SP. Pretreatment with a desensitizing regimen of SP potentiates the antinociceptive effect of morphine and baclofen when they are tested immediately after the regimen but if a 30 min delay is permitted, an inhibition of their effects is observed. These results support the notion that the spinal antinociceptive effect of morphine and baclofen is due to an interaction with SP mechanisms in the spinal cord, the nature of which may be more complex than is presently understood. Desensitization produces no change in baseline responsiveness in the tail flick test. This suggests that the hyperalgesic response to SP is due either to an action at a site other than the primary afferent synapse, or if it is at this site either compensatory mechanisms occur or SP is not the primary determinant of tail flick latency but may play a modulatory role.

Animals↗