Caffeine as an analgesic adjuvant: a review of pharmacology and mechanisms of action.
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Analgesics↗
Biomedical subjects
J Sawynok
Publications and source records attributed to J Sawynok.
Noradrenergic mediation of spinal antinociception by 5-hydroxytryptamine: characterization of receptor subtypes.
The present study examined the involvement of spinal noradrenergic mechanisms in spinal antinociception by the 5-hydroxy-tryptamine (5-HT) receptor-selective agonists CGS 12066B (5-HT1B; 7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo[1,2-a]quinoxaline), TFMPP (5-HT1C; M-trifluoromethylphenyl-piperazine) and DOI (5-HT2; 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) using the rat hot plate test. Effects of alpha-adrenoreceptor antagonists (phentolamine, yohimbine), the adrenergic neurotoxin 6-hydroxydopamine, and the selective noradrenergic uptake blocker desipramine were determined. CGS 12066B, TFMPP and DOI produced dose-related antinociception. The antinociceptive effect of each agent was reduced by pretreatment with both phentolamine and yohimbine (15-60 micrograms). Pretreatment with 6-hydroxydopamine (100 micrograms, intrathecal) for 7-10 days, which reduced spinal cord levels of noradrenaline by 87%, inhibited the action of TFMPP (and 5-HT), but not CGS 12066B or DOI. Pretreatment with desipramine (25 mg/kg, systemic) potentiated the action of TFMPP but not CGS 12066B or DOI (or 2-methyl-5-HT). These results suggest that antinociception by TFMPP is dependent on release of endogenous noradrenaline from the spinal cord, while that produced by CGS 12066B and DOI is not. As TFMPP exhibits a close similarity to 5-HT in these experiments, the 5-HT receptor subtype being activated to induce noradrenaline release may either be a 5-HT1C or a 5-HT1S subtype. Other mechanisms account for the observed blockade of the action of CGS 12066B and DOI by alpha-adrenoreceptor antagonists.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Noradrenergic and purinergic involvement in spinal antinociception by 5-hydroxytryptamine and 2-methyl-5-hydroxytryptamine.
The adrenergic involvement in spinal antinociception by 5-hydroxytryptamine (5-HT) and 2-methyl-5-hydroxytryptamine (2-Me-5-HT) was examined using the alpha-adrenoceptor antagonists phentolamine, yohimbine and prazosin, and the neurotoxin 6-hydroxydopamine. Intrathecal pretreatment with phentolamine and yohimbine (7.5-30 micrograms), but not prazosin (30 micrograms), reduced the action of 5-HT and 2-Me-5-HT in both the tail flick and hot plate tests. Pretreatment with 6-hydroxydopamine (100 micrograms) reduced (5-HT) or increased (2-Me-5-HT) antinociception in the hot plate test, while tail flick responses were largely unaffected. In other experiments, 8-phenyltheophylline, an adenosine receptor antagonist, reduced the action of 5-HT, but not 2-Me-5-HT, in both tests. These results indicate that (a) antinociception by both 5-HT and 2-Me-5-HT involves some form of interaction with spinal alpha 2-adrenoceptors, but the nature of the interaction for these two agents is different because only 5-HT is dependent on endogenous noradrenaline, (b) release of adenosine from the spinal cord contributes to spinal antinociception by 5-HT but not by 2-Me-5-HT.
Analgesics↗
Spinal antinociception by adenosine analogs and morphine after intrathecal administration of the neurotoxins capsaicin, 6-hydroxydopamine and 5,7-dihydroxytryptamine.
The effects of intrathecal pretreatment with the neurotoxins capsaicin, 6-hydroxydopamine and 5,7-dihydroxytryptamine on spinal antinociception by adenosine analogs (NECA, 5'-N-ethylcarboxamido adenosine and CHA, N6-cyclohexyl adenosine) and morphine were examined using the rat tail flick and hot plate tests. Pretreatment with 50 micrograms capsaicin for 7 to 11 days (which reduced substance P immunoreactivity in the superficial layers of the dorsal spinal cord) produced a slight increase in the action of NECA and CHA, and reduced the action on morphine in the hot plate test but not in the tail flick test. Pretreatment with 50 to 100 micrograms 6-hydroxydopamine for 7 to 14 days (which reduced spinal cord noradrenaline levels by 54-65%) reduced spinal antinociception by NECA and CHA but not that by morphine. Pretreatment with 50 micrograms 5,7-dihydroxytryptamine (which reduced spinal cord serotonin levels by 74-89%) had no effect on any agent. Acute pretreatment with 7.5-30 micrograms phentolamine reduced the spinal antinociceptive action of noradrenaline, NECA and CHA, primarily in the hot plate test. Phentolamine (30 micrograms) also reduced the action of morphine (hot plate greater than tail flick), but did not affect the action of L-baclofen. These results suggest that spinal antinociception by adenosine analogs: 1) occurs primarily at a postsynaptic site of action (capsaicin results), and 2) is dependent on release of endogenous noradrenaline and activation of spinal adrenergic receptors (6-hydroxydopamine and phentolamine results). The reduction in the effect of morphine by capsaicin (removes a source of adenosine release) and phentolamine (antagonizes the action of endogenously released adenosine) can be explained in terms of the adenosine release hypothesis of morphine action within the spinal cord.
5,7-Dihydroxytryptamine↗
8-Phenyltheophylline reverses the antinociceptive action of morphine in the periaqueductal gray.
Morphine was injected into the periaqueductal gray region of the rat and 8-phenyltheophylline, an adenosine receptor antagonist, was injected intrathecally 15 or 30 min later, to determine whether supraspinally-administered morphine activated descending mechanisms to release adenosine (or a nucleotide which is metabolized to adenosine) from the spinal cord. 8-Phenyltheophylline (10 micrograms) reversed the antinociceptive action of morphine in the hot plate but not the tail-flick test. A combination of methysergide/phentolamine (15 micrograms each) reversed the action of morphine in both tests. 8-Phenyltheophylline retained the ability to reverse the action of morphine in the hot plate test in rats pretreated with 6-hydroxydopamine (to induce degeneration of descending noradrenergic pathways) but reversal was no longer observed in rats pretreated with 5,7-dihydroxytryptamine (after pretreatment with desipramine, to induce degeneration of descending serotonergic pathways). These results indicate that a component of the supraspinal antinociceptive action of morphine is due to release of adenosine or nucleotide, within the spinal cord and this release is dependent on intact serotonergic pathways.
5,7-Dihydroxytryptamine↗
Effects of forskolin and phosphodiesterase inhibitors on spinal antinociception by morphine.
The effect of intrathecal pretreatment with forskolin and the phosphodiesterase inhibitors Ro 20-1724, rolipram and 3-isobutyl-1-methylxanthine (IBMX) on the antinociceptive action of morphine administered intrathecally was examined using the rat tail-flick test to determine whether inhibition of adenylate cyclase contributed to spinal antinociception. Intrathecal pretreatment with forskolin (10 micrograms), Ro 20-1724 (15 micrograms) and IBMX (10 micrograms) inhibited the action of morphine in the tail-flick test. However, pretreatment with Ro 20-1724 (30 micrograms), rolipram (10 and 30 micrograms) and IBMX (30 micrograms) increased the action of morphine. These agents were devoid of intrinsic antinociceptive activity. Inhibition of spinal antinociception by morphine with agents which increase cyclic AMP levels in biochemical experiments is consistent with the hypothesis that some opiate actions are due to inhibition of adenylate cyclase. However, in view of the consistent increase in the effect of morphine with phosphodiesterase inhibitors at higher doses, this hypothesis may be insufficient to account for opiate interactions with the adenylate cyclase system in the spinal cord. Some effects on spinal antinociception also may be due to additional pharmacological actions of the agents used.
1-Methyl-3-isobutylxanthine↗
Forskolin and phosphodiesterase inhibitors release adenosine but inhibit morphine-evoked release of adenosine from spinal cord synaptosomes.
The effects of forskolin, Ro 20-1724, rolipram, and 3-isobutyl-1-methylxanthine (IBMX) on morphine-evoked release of adenosine from dorsal spinal cord synaptosomes were evaluated to examine the potential involvement of cyclic AMP in this action of morphine. Ro 20-1724 (1-100 microM), rolipram (1-100 microM), and forskolin (1-10 microM) increased basal release of adenosine, and at 1 microM inhibited morphine-evoked release of adenosine. Release of adenosine by Ro 20-1724, rolipram, and forskolin was reduced 42-77% in the presence of alpha,beta-methylene ADP and GMP, which inhibits ecto-5'-nucleotidase activity by 81%, indicating that this adenosine originated predominantly as nucleotide(s). Significant amounts of adenosine also were released from the ventral spinal cord by these agents. Ro 20-1724 and rolipram did not significantly alter the uptake of adenosine into synaptosomes. Although Ro 20-1724 and rolipram had only limited effects on the extrasynaptosomal conversion of added cyclic AMP to adenosine, IBMX, a phosphodiesterase inhibitor with a broader spectrum of inhibitory activity for phosphodiesterase isoenzymes, significantly inhibited the conversion of cyclic AMP to adenosine and resulted in recovery of a substantial amount of cyclic AMP. As with the non-xanthine phosphodiesterase inhibitors, IBMX increased basal release of adenosine and reduced morphine-evoked release of adenosine. Adenosine released by IBMX was reduced 70% in the presence of alpha,beta-methylene ADP and GMP, and release from the ventral spinal cord was 61% of that from the dorsal spinal cord. Collectively, these results indicate that forskolin and phosphodiesterase inhibitors release nucleotide(s) which is (are) converted extrasynaptosomally to adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)
1-Methyl-3-isobutylxanthine↗
Intracerebroventricular morphine releases adenosine and adenosine 3',5'-cyclic monophosphate from the spinal cord via a serotonergic mechanism.
Intracerebroventricular (i.c.v.) administration of morphine produces antinociception which is antagonized by intrathecal (i.t.) injection of adenosine receptor antagonists, suggesting that adenosine release from the spinal cord may partially mediate antinociception produced by supraspinal morphine. In the present study we have examined this hypothesis directly. Administration of 40 nmol of morphine i.c.v. acutely to rats increased tail-flick and hot-plate nociceptive latencies. This antinociception was antagonized by i.t. theophylline (12 nmol) and 8-phenyltheophylline (1.2 and 12 nmol), but was potentiated by a high dose of theophylline (120 nmol). The same dose of i.c.v. morphine increased the release of adenosine into i.t. perfusates by 40 to 60% above basal release values, and also released a nucleotide which was identified as cyclic AMP by using high performance liquid chromatography. This release of adenosine and cyclic AMP was reduced after i.t. pretreatment with 5,7-dihydroxytryptamine (100 micrograms) but not 6-hydroxydopamine (100 micrograms). Spinal release of purines induced by i.c.v. morphine also was reduced by i.t. perfusion with 50 microM methysergide whereas 50 microM phentolamine had no effect. These data suggest that i.c.v. morphine activates descending serotonergic pathways to release purines from the spinal cord, and that such release is secondary to release of 5-hydroxytryptamine. Extracellular adenosine may contribute significantly to antinociception produced by supraspinal morphine.
Adenosine↗
5-Hydroxytryptamine releases adenosine and cyclic AMP from primary afferent nerve terminals in the spinal cord in vivo.
5-Hydroxytryptamine (5-HT) releases a purine nucleotide, which is subsequently converted to adenosine, from primary afferent nerve terminals in vitro. This release may mediate spinal antinociception by 5-HT. In the present study, we have investigated whether release also occurs from the spinal cord in vivo using an intrathecal perfusion system in rats. Adenosine was quantitated using high performance liquid chromatography (HPLC) with fluorescence detection. Following perfusion of the spinal cord with 50 and 500 microM 5-HT, a 35-50% increase in the release of endogenous adenosine was observed. This release was completely blocked by 50 microM methysergide, and by intrathecal injection with 100 micrograms capsaicin 5-8 days prior to release experiments. Intrathecal perfusion with 50 and 500 microM 5-HT also released a nucleotide which eluted from the HPLC column at a retention time identical to that of cyclic AMP standards, and was reduced following incubation with cyclic AMP phosphodiesterase. This release of cyclic AMP also was eliminated following intrathecal pretreatment with capsaicin. In contrast to 5-HT, noradrenaline (NA, 500 microM and 5 mM) did not release adenosine or cyclic AMP from the intact spinal cord. These data demonstrate that release of nucleotide, probably cyclic AMP, and subsequent metabolism to adenosine, can be induced by 5-HT but not NA in vivo. This strengthens the hypothesis that release of adenosine from the spinal cord may mediate antinociception by intrathecal 5-HT but not NA.
Adenosine↗
Adenosine mediates calcium-induced antinociception and potentiation of noradrenergic antinociception in the spinal cord.
Intrathecal (i.t.) coadministration of calcium (Ca2+), 50 micrograms potentiates the spinal antinociceptive action of morphine and noradrenaline (NA) but not cyclohexyladenosine, 5'-N-ethylcarboxamido adenosine or 5-hydroxytryptamine in the rat tail flick test. This dose of Ca2+ has no intrinsic effect in this test. Higher doses of Ca2+ (200-400 micrograms) produce antinociception in the tail flick and hot plate tests, which is completely blocked by pretreatment with the adenosine receptor antagonists theophylline, 50 micrograms and 8-phenyltheophylline, 3 micrograms. 8-Phenyltheophylline also eliminates potentiation of the antinociceptive action of NA by 50 micrograms Ca2+. The intrinsic antinociceptive effect of Ca2+ is blocked by i.t. pretreatment with the neurotoxins capsaicin, 50 micrograms and 6-hydroxydopamine, 50 micrograms but not 5,7-dihydroxytryptamine, 50 micrograms. Antinociception also is blocked by pretreatment with phentolamine but not by methysergide. These results suggest that the antinociceptive action of high doses of Ca2+ is due to release of adenosine (or a nucleotide which is metabolized to adenosine) from the spinal cord. At lower doses, the release of adenosine is insufficient to cause antinociception, but potentiates the action of NA. Adenosine appears to originate from capsaicin-sensitive small diameter primary afferent nerve terminals. A subsequent interaction of adenosine with spinal adrenergic receptors contributes to antinociception.
5,7-Dihydroxytryptamine↗
Supersensitivity to intrathecal 5-hydroxytryptamine, but not noradrenaline, following depletion of spinal 5-hydroxytryptamine by 5,7-dihydroxytryptamine administered into various sites.
The present study was conducted (a) to determine if cross-supersensitivity at spinal noradrenergic receptors could be demonstrated in antinociceptive tests following depletion of spinal cord 5-hydroxytryptamine (5HT) by the intrathecal (i.t.) and intracerebroventricular (i.c.v.) administration of 5,7-dihydroxytryptamine (5,7DHT), and (b) to compare the pattern of supersensitivity at spinal 5HT receptors following these manipulations and 5,7DHT microinjected into the ventral raphe (VR) region and the nucleus raphe magnus (NRM). Both i.t. and i.c.v. administration of 5,7DHT produced a marked depletion of spinal cord 5HT (greater than 75%) and supersensitivity to the i.t. injection of 5HT in the tail flick and hot plate tests. No supersensitivity to the i.t. injection of noradrenaline (NA) was observed. Microinjection of 5,7DHT into the VR and NRM produced less depletion of spinal cord 5HT (40-57%), and supersensitivity to the i.t. injection of 5HT was observed only in the hot plate test following microinjection of 5,7DHT into the VR. An increased incidence of signs of the 5HT behavioural syndrome, particularly tremor and Straub tail, was observed in all 5,7DHT-pretreated groups. These results indicate that cross-supersensitivity to spinal NA receptors does not occur following depletion of spinal cord 5HT. In addition, responses mediated by 5HT receptors show a differential pattern of development of supersensitivity. Thus, the 5HT behavioural syndrome (presumably mediated by 5HT1A receptors) more readily reflects the development of supersensitivity than the tail flick test (presumably mediated by 5HT2 receptors), while the hot plate test (uncharacterized subtype) shows an intermediate development of supersensitivity.
5,7-Dihydroxytryptamine↗
Adenosine release by morphine and spinal antinociception: role of G-proteins and cyclic AMP.
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Adenosine↗
Pertussis toxin inhibits morphine-induced release of adenosine from the spinal cord.
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Adenosine↗
Lesions to ascending noradrenergic and serotonergic pathways modify antinociception produced by intracerebroventricular administration of morphine.
Ascending noradrenergic and serotonergic pathways were lesioned by injection of 6-hydroxydopamine into the dorsal bundle or 5,7-dihydroxytryptamine into the ventromedial tegmentum respectively, and the antinociceptive effect of morphine, administered by intracerebroventricular injection assessed using the tail-flick test 3-14 days later. Lesions of the dorsal bundle selectively depleted levels of noradrenaline (NA) in the forebrain and increased the antinociceptive effect of morphine early, but not later, in the time course of action. Lesions to the locus coeruleus depleted NA in the forebrain and spinal cord but had no effect on the antinociceptive action of morphine. Lesions of the ventromedial tegmentum selectively depleted 5-hydroxytryptamine (5-HT) in the forebrain and transiently reduced the action of morphine. 5,7-Dihydroxytryptamine given intraventricularly depleted 5-HT in the forebrain and spinal cord and also transiently reduced the antinociceptive effect of morphine. These results indicate that aminergic pathways, projecting to the forebrain, are involved in the suppression of the tail-flick reflex produced by injection of morphine into the lateral ventricle.
5,7-Dihydroxytryptamine↗
Adenosine release may mediate spinal analgesia by morphine.
Spinal analgesia produced by morphine is blocked by methylxanthine adenosine receptor antagonists. In biochemical studies, morphine releases adenosine from spinal cord synaptosomes prepared from the dorsal spinal cord, as well as from the intact spinal cord in vivo. Adenosine release is reduced by intrathecal and neonatal pretreatment with capsaicin but not by intrathecal pretreatment with 6-hydroxydopamine or 5,7-dihydroxytryptamine, indicating that adenosine originates from small-diameter primary afferent neurons but not descending monoaminergic pathways. In this Viewpoint Jana Sawynok and colleagues review the evidence supporting the hypothesis that the spinal analgesic action of morphine is due to the release of adenosine from primary afferent nerve terminals and subsequent activation of A1 and A2 adenosine receptors.
Adenosine↗
The role of purines in nociception.
The preceding review indicates that there is convincing evidence for the presence of adenosine in and release of adenosine from capsaicin-sensitive small diameter primary afferent neurons in the spinal cord (Fig. 1). Within the dorsal spinal cord, adenosine inhibits the transmission of nociceptive information, although details of mechanisms involved in this action remain to be established. In view of the antinociceptive actions of adenosine analogues, there has been some interest in the possibility of developing adenosine analogues as analgesic agents. However, this goal may be frustrated by this concomitant suppression of motor function, as well as the production of other side effects due to the diverse nature of pharmacological effects seen with adenosine analogues. Release of adenosine from small diameter primary afferent nerve terminals and subsequent activation of extracellular adenosine receptors in the dorsal horn of the spinal cord appears to contribute significantly to the spinal action of opioids. An understanding of spinal mechanisms of actions of adenosine therefore is an important prerequisite for our understanding of the action of this clinically important group of drugs. ATP may be a sensory neurotransmitter released from non-nociceptive large diameter primary afferent neurons (Fig. 1). The subsequent extracellular conversion of released ATP to adenosine may produce suppression of the transmission of noxious sensory information via small diameter primary afferent fibres, and contribute to the phenomenon of vibration induced analgesia. Clearly, the role of purines on spinal cord processing of nociceptive information merits considerable attention.
Adenosine↗
The 1988 Merck Frosst Award. The role of ascending and descending noradrenergic and serotonergic pathways in opioid and non-opioid antinociception as revealed by lesion studies.
Both ascending and descending noradrenergic and serotonergic pathways have been implicated in mechanisms of antinociception produced by systemic administration of morphine and the non-opioid drugs, baclofen and clonidine. These agents affect the turnover and release of noradrenaline and 5-hydroxytryptamine in various brain regions and the spinal cord, and alter neuronal activity in regions from which ascending and descending aminergic pathways originate. The role of specific pathways in morphine analgesia has been examined by applying electrolytic lesions to discrete brain regions. However, this technique is limited because lesions are nonselective for a particular neuronal population. More recent studies have used microinjection of the neurotoxins 6-hydroxydopamine and 5,7-dihydroxytryptamine to lesion specific noradrenergic and serotonergic pathways, respectively. Although more selective, this approach may be limited by the development of receptor supersensitivity or other mechanisms of compensation, as certain changes seen soon after microinjection (days) are no longer apparent at later intervals (weeks). Systemic drug administration reveals drug actions at predominant but not clearly identified sites of action. The role of a particular aminergic pathway can be revealed most clearly by combining microinjection of drugs into discrete brain sites with neurotoxin-induced lesions, and examining the effects of such lesions at a range of time intervals. A differential role of a particular pathway may become apparent following systemic or intracerebral administration.
Analgesics↗
Morphine, capsaicin and K+ release purines from capsaicin-sensitive primary afferent nerve terminals in the spinal cord.
In the present study the neuronal source of adenosine released by K+, morphine and norepinephrine (NE) from the spinal cord was investigated. Intrathecal pretreatment with 5,7-dihydroxytryptamine and 6-hydroxydopamine reduced spinal 5-hydroxytryptamine and NE levels, respectively, but had no effect on adenosine release from dorsal spinal cord synaptosomes evoked by K+ or morphine. NE-evoked release of adenosine was unaffected by 5,7-dihydroxytryptamine but increased by 6-hydroxydopamine. Subcutaneous pretreatment of neonatal or intrathecal pretreatment of adult rats with capsaicin increased nociceptive thresholds and reduced the release of adenosine evoked by K+ and morphine but not NE from dorsal spinal cord synaptosomes. Intrathecal capsaicin also inhibited morphine-evoked release of adenosine in vivo. K+ and morphine released only small amounts of adenosine from ventral spinal cord synaptosomes whereas NE released significant amounts. Exposure of dorsal, but not ventral, spinal cord synaptosomes to capsaicin produced a dose- and Ca++-dependent release of adenosine, which was reduced by capsaicin pretreatment (neonatal and adult) and inhibition of ecto-5'-nucleotidase. Capsaicin also released endogenous ATP from dorsal spinal cord synaptosomes. These results suggest that primary afferent nerve terminals in the dorsal horn of the spinal cord release adenosine in response to morphine and K+, and a nucleotide (possibly ATP) in response to capsaicin. Adenosine does not appear to be released from the terminals of descending aminergic pathways. The source of purines released by NE is less certain.
Adenosine↗