The preceding review indicates that there is convincing evidence for the presence of adenosine in... more 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.
The Journal of pharmacology and experimental therapeutics, 1987
Intrathecal (i.t.) pretreatment of rats with either theophylline (50 micrograms) or 8-phenyltheop... more 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. Noradrena...
The Journal of pharmacology and experimental therapeutics, 1991
Intracerebroventricular (i.c.v.) administration of morphine produces antinociception which is ant... more 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-dihydrox...
Background: A double-blind, randomized, placebo-controlled 3-week study evaluated the efficacy of... more Background: A double-blind, randomized, placebo-controlled 3-week study evaluated the efficacy of topical 2% amitriptyline, 1% ketamine, and a combination of both in treating patients with neuropathic pain. Methods: Ninety-two patients with diabetic neuropathy, postherpetic neuralgia, or postsurgical/posttraumatic neuropathic pain with allodynia, hyperalgesia, or pinprick hypesthesia were randomly assigned to receive one of four creams (placebo, 2% amitriptyline, 1% ketamine, or 2% amitriptyline-1% ketamine combined). The primary outcome measure was change in average daily pain intensity (baseline week vs. final week) using an 11-point numerical pain rating scale. Secondary outcomes included the McGill Pain Questionnaire, measures of allodynia and hyperalgesia, and patient satisfaction. Results: A reduction in pain scores of 1.1-1.5 units was observed in all groups, and there was no difference between groups. Blood concentrations revealed no significant systemic absorption. Minimal side effects were encountered. Conclusion: This randomized, placebo-controlled trial examining topical 2% amitriptyline, 1% ketamine, and a combination in the treatment of neuropathic pain revealed no difference between groups. Optimization of doses may be required, because another study has revealed that higher concentrations of these agents combined do produce significant analgesia.
There is an emerging literature on health benefits of qigong in fibromyalgia in which participant... more There is an emerging literature on health benefits of qigong in fibromyalgia in which participants practice qigong for standardized amounts of time (up to 6 months) and some reports of practice for 1-3 years. However, there is little information on longer-term practice over decades. This is a report of the experiences of three individuals with chronic pain and multiple other health problems who undertook instruction in qigong (Chaoyi Fanhuan Qigong, CFQ) and went on to practice over extended periods of time (hours/day, 8-15 years). All three report resolution of their chronic pain and multiple other health problems, as well as improvements in vision, during the course of their longterm practice. In each case, some benefits were manifest within the first months of practice, and initial benefits promoted further and more diligent practice to explore health possibilities. Health benefits occurred progressively over time. Improvements in eyesight were gradual. These experiences indicate...
The Pharmacological Society of Canada (PSC) formed in 1956 and became a constituent society of th... more The Pharmacological Society of Canada (PSC) formed in 1956 and became a constituent society of the Canadian Federation of Biological Sciences (CFBS) in 1958. Over subsequent decades, it met annually with CFBS, matured as a society, and established an identity as the voice of pharmacology in Canada. During the 1980s, it sought a larger stage and bid for, and then hosted, the XIIth International Congress of Pharmacology in Montreal in 1994. The society then participated in several joint meetings with other national pharmacology societies. In 2008, the PSC merged with the Canadian Society for Clinical Pharmacology to form the Canadian Society for Pharmacology and Therapeutics. The following article is a history of the PSC from its formation in the mid-1950s to amalgamation in 2008.
Qigong is an internal art practice with a long history in China. It is currently characterized as... more Qigong is an internal art practice with a long history in China. It is currently characterized as meditative movement (or as movement-based embodied contemplative practice), but is also considered as complementary and alternative exercise or mind-body therapy. There are now six controlled trials and nine other reports on the effects of qigong in fibromyalgia. Outcomes are related to amount of practice so it is important to consider this factor in overview analyses. If one considers the 4 trials (201 subjects) that involve diligent practice (30-45 min daily, 6-8 weeks), there are consistent benefits in pain, sleep, impact, and physical and mental function following the regimen, with benefits maintained at 4-6 months. Effect sizes are consistently in the large range. There are also reports of even more extensive practice of qigong for 1-3 years, even up to a decade, indicating marked benefits in other health areas beyond core domains for fibromyalgia. While the latter reports involve a limited number of subjects and represent a self-selected population, the marked health benefits that occur are noteworthy. Qigong merits further study as a complementary practice for those with fibromyalgia. Current treatment guidelines do not consider amount of practice, and usually make indeterminate recommendations.
Local administration of amitriptyline into the rat hindpaw produces peripheral antinociception; t... more Local administration of amitriptyline into the rat hindpaw produces peripheral antinociception; this is reduced by adenosine receptor antagonists and appears to involve endogenous adenosine. The present study used peripheral microdialysis: (a) to determine whether amitriptyline could enhance extracellular tissue levels of endogenous adenosine in the rat hindpaw and (b) to examine mechanisms by which such an increase could occur. Local injection of amitriptyline into the plantar hindpaw, at doses that produce peripheral antinociception (100-300 nmol), produced an increase in local extracellular levels of adenosine. When injected in combination with formalin, which also enhances such levels of adenosine, an additive increase was observed. This adenosine originated partly as nucleotide, as inhibition of ecto-5Vnucleotidase reduced the amount of adenosine detected in the probe following administration of amitriptyline. When administered in combination with exogenous adenosine, amitriptyline augmented recovery of adenosine in the probe. Pretreatment of rats with capsaicin augmented the ability of amitriptyline to increase adenosine levels detected in the dialysis probe; it also enhanced tissue recovery of exogenously administered adenosine. In uptake studies using cultured rat C6 glioma cells, amitriptyline inhibited adenosine uptake by an adenosine transporter (IC 50 0.37 T 0.12 mM). In enzyme assays, amitriptyline had no effect on adenosine kinase or adenosine deaminase activity. These results demonstrate that amitriptyline: (a) enhances extracellular tissue levels of adenosine in the rat hindpaw following local administration in vivo and (b) inhibits adenosine uptake but has no effect on metabolism in vitro. Therefore, increased extracellular adenosine levels in vivo appear to result partially from extracellular conversion of nucleotide and partially from inhibition of uptake.
Caffeine produces antinociception in the formalin test at lower doses than in thermal threshold t... more Caffeine produces antinociception in the formalin test at lower doses than in thermal threshold tests. In this study, we examined (a) the effect of formalin concentration on the action of caffeine, and (b) the relative involvement of adenosine A1 and A2 receptors in the action of caffeine. Formalin 1%, 2% and 5% produces a concentration-dependent increase in flinching behaviour in rats. At 5% formalin, the EC50 for caffeine in reducing phase 2 responses (16-60 min following formalin injection) is 40 mg/kg, but at 2%, this is reduced to 5 mg/kg. There is no further shift using 1% formalin. Caffeine has a more pronounced effect on phase 2A (16-36 min) than on phase 2, with significant effects being observed at lower doses. Both 8-cyclopentyltheophylline (A1 selective) and 3,7-dimethyl-1-propargylxanthine (A2 selective) produce a dose-related inhibition of 1.5% formalin flinching behaviours between 1-10 mg/kg. Both agents also produce locomotor stimulation over this dose range, but significant effects occur only at 10 mg/kg. These results indicate that antinociception by caffeine shows a high dependence on stimulus intensity. At 1-2% formalin, doses of caffeine that produce antinociception are now in the range that corresponds to normal human dietary and therapeutic intake levels. Both antinociception and locomotor stimulation appear to be dependent on activation of adenosine A1 receptors, as effects of 3,7-dimethyl-1-propargylxanthine are observed only at a dose which blocks adenosine A1 receptors in addition to A2 receptors.
ABSTRACT The formalin test was introduced as a model of tonic pain in 1977, and has since been us... more ABSTRACT The formalin test was introduced as a model of tonic pain in 1977, and has since been used extensively in rats and mice. In rats, formalin generates an initial phase of activity (510 min, phase 1), a quiescent interphase (510 min), and a second phase of activity (lasting 6090 min, phase 2), and this is seen with spontaneous behaviors, firing of afferent neurons, and activity in dorsal horn neurons. Both active phases involve ongoing peripheral afferent neural activity; inflammation contributes to phase 2 activity and the interphase results from active inhibition. Responses are concentration dependent between 0.25% and 2.5%, plateau from 2.5% to 5%, and can decline at higher concentrations. Formalin also results in tissue edema, and this is longer lasting. Responses to formalin up to 2.5% are predominantly neurogenic, while at higher concentrations, responses involve a further prominent inflammatory component. Within the spinal cord, formalin increases c-Fos expression in neurons and causes activation of microglia, and these may contribute more prominently to longer term changes. Acute responses (to 90 min) may represent a model of ongoing acute pain involving inflammation and aspects of central sensitization, while longer term responses (days, weeks) may represent a model of changes involved in persistent pathological pain.
The preceding review indicates that there is convincing evidence for the presence of adenosine in... more 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.
The Journal of pharmacology and experimental therapeutics, 1987
Intrathecal (i.t.) pretreatment of rats with either theophylline (50 micrograms) or 8-phenyltheop... more 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. Noradrena...
The Journal of pharmacology and experimental therapeutics, 1991
Intracerebroventricular (i.c.v.) administration of morphine produces antinociception which is ant... more 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-dihydrox...
Background: A double-blind, randomized, placebo-controlled 3-week study evaluated the efficacy of... more Background: A double-blind, randomized, placebo-controlled 3-week study evaluated the efficacy of topical 2% amitriptyline, 1% ketamine, and a combination of both in treating patients with neuropathic pain. Methods: Ninety-two patients with diabetic neuropathy, postherpetic neuralgia, or postsurgical/posttraumatic neuropathic pain with allodynia, hyperalgesia, or pinprick hypesthesia were randomly assigned to receive one of four creams (placebo, 2% amitriptyline, 1% ketamine, or 2% amitriptyline-1% ketamine combined). The primary outcome measure was change in average daily pain intensity (baseline week vs. final week) using an 11-point numerical pain rating scale. Secondary outcomes included the McGill Pain Questionnaire, measures of allodynia and hyperalgesia, and patient satisfaction. Results: A reduction in pain scores of 1.1-1.5 units was observed in all groups, and there was no difference between groups. Blood concentrations revealed no significant systemic absorption. Minimal side effects were encountered. Conclusion: This randomized, placebo-controlled trial examining topical 2% amitriptyline, 1% ketamine, and a combination in the treatment of neuropathic pain revealed no difference between groups. Optimization of doses may be required, because another study has revealed that higher concentrations of these agents combined do produce significant analgesia.
There is an emerging literature on health benefits of qigong in fibromyalgia in which participant... more There is an emerging literature on health benefits of qigong in fibromyalgia in which participants practice qigong for standardized amounts of time (up to 6 months) and some reports of practice for 1-3 years. However, there is little information on longer-term practice over decades. This is a report of the experiences of three individuals with chronic pain and multiple other health problems who undertook instruction in qigong (Chaoyi Fanhuan Qigong, CFQ) and went on to practice over extended periods of time (hours/day, 8-15 years). All three report resolution of their chronic pain and multiple other health problems, as well as improvements in vision, during the course of their longterm practice. In each case, some benefits were manifest within the first months of practice, and initial benefits promoted further and more diligent practice to explore health possibilities. Health benefits occurred progressively over time. Improvements in eyesight were gradual. These experiences indicate...
The Pharmacological Society of Canada (PSC) formed in 1956 and became a constituent society of th... more The Pharmacological Society of Canada (PSC) formed in 1956 and became a constituent society of the Canadian Federation of Biological Sciences (CFBS) in 1958. Over subsequent decades, it met annually with CFBS, matured as a society, and established an identity as the voice of pharmacology in Canada. During the 1980s, it sought a larger stage and bid for, and then hosted, the XIIth International Congress of Pharmacology in Montreal in 1994. The society then participated in several joint meetings with other national pharmacology societies. In 2008, the PSC merged with the Canadian Society for Clinical Pharmacology to form the Canadian Society for Pharmacology and Therapeutics. The following article is a history of the PSC from its formation in the mid-1950s to amalgamation in 2008.
Qigong is an internal art practice with a long history in China. It is currently characterized as... more Qigong is an internal art practice with a long history in China. It is currently characterized as meditative movement (or as movement-based embodied contemplative practice), but is also considered as complementary and alternative exercise or mind-body therapy. There are now six controlled trials and nine other reports on the effects of qigong in fibromyalgia. Outcomes are related to amount of practice so it is important to consider this factor in overview analyses. If one considers the 4 trials (201 subjects) that involve diligent practice (30-45 min daily, 6-8 weeks), there are consistent benefits in pain, sleep, impact, and physical and mental function following the regimen, with benefits maintained at 4-6 months. Effect sizes are consistently in the large range. There are also reports of even more extensive practice of qigong for 1-3 years, even up to a decade, indicating marked benefits in other health areas beyond core domains for fibromyalgia. While the latter reports involve a limited number of subjects and represent a self-selected population, the marked health benefits that occur are noteworthy. Qigong merits further study as a complementary practice for those with fibromyalgia. Current treatment guidelines do not consider amount of practice, and usually make indeterminate recommendations.
Local administration of amitriptyline into the rat hindpaw produces peripheral antinociception; t... more Local administration of amitriptyline into the rat hindpaw produces peripheral antinociception; this is reduced by adenosine receptor antagonists and appears to involve endogenous adenosine. The present study used peripheral microdialysis: (a) to determine whether amitriptyline could enhance extracellular tissue levels of endogenous adenosine in the rat hindpaw and (b) to examine mechanisms by which such an increase could occur. Local injection of amitriptyline into the plantar hindpaw, at doses that produce peripheral antinociception (100-300 nmol), produced an increase in local extracellular levels of adenosine. When injected in combination with formalin, which also enhances such levels of adenosine, an additive increase was observed. This adenosine originated partly as nucleotide, as inhibition of ecto-5Vnucleotidase reduced the amount of adenosine detected in the probe following administration of amitriptyline. When administered in combination with exogenous adenosine, amitriptyline augmented recovery of adenosine in the probe. Pretreatment of rats with capsaicin augmented the ability of amitriptyline to increase adenosine levels detected in the dialysis probe; it also enhanced tissue recovery of exogenously administered adenosine. In uptake studies using cultured rat C6 glioma cells, amitriptyline inhibited adenosine uptake by an adenosine transporter (IC 50 0.37 T 0.12 mM). In enzyme assays, amitriptyline had no effect on adenosine kinase or adenosine deaminase activity. These results demonstrate that amitriptyline: (a) enhances extracellular tissue levels of adenosine in the rat hindpaw following local administration in vivo and (b) inhibits adenosine uptake but has no effect on metabolism in vitro. Therefore, increased extracellular adenosine levels in vivo appear to result partially from extracellular conversion of nucleotide and partially from inhibition of uptake.
Caffeine produces antinociception in the formalin test at lower doses than in thermal threshold t... more Caffeine produces antinociception in the formalin test at lower doses than in thermal threshold tests. In this study, we examined (a) the effect of formalin concentration on the action of caffeine, and (b) the relative involvement of adenosine A1 and A2 receptors in the action of caffeine. Formalin 1%, 2% and 5% produces a concentration-dependent increase in flinching behaviour in rats. At 5% formalin, the EC50 for caffeine in reducing phase 2 responses (16-60 min following formalin injection) is 40 mg/kg, but at 2%, this is reduced to 5 mg/kg. There is no further shift using 1% formalin. Caffeine has a more pronounced effect on phase 2A (16-36 min) than on phase 2, with significant effects being observed at lower doses. Both 8-cyclopentyltheophylline (A1 selective) and 3,7-dimethyl-1-propargylxanthine (A2 selective) produce a dose-related inhibition of 1.5% formalin flinching behaviours between 1-10 mg/kg. Both agents also produce locomotor stimulation over this dose range, but significant effects occur only at 10 mg/kg. These results indicate that antinociception by caffeine shows a high dependence on stimulus intensity. At 1-2% formalin, doses of caffeine that produce antinociception are now in the range that corresponds to normal human dietary and therapeutic intake levels. Both antinociception and locomotor stimulation appear to be dependent on activation of adenosine A1 receptors, as effects of 3,7-dimethyl-1-propargylxanthine are observed only at a dose which blocks adenosine A1 receptors in addition to A2 receptors.
ABSTRACT The formalin test was introduced as a model of tonic pain in 1977, and has since been us... more ABSTRACT The formalin test was introduced as a model of tonic pain in 1977, and has since been used extensively in rats and mice. In rats, formalin generates an initial phase of activity (510 min, phase 1), a quiescent interphase (510 min), and a second phase of activity (lasting 6090 min, phase 2), and this is seen with spontaneous behaviors, firing of afferent neurons, and activity in dorsal horn neurons. Both active phases involve ongoing peripheral afferent neural activity; inflammation contributes to phase 2 activity and the interphase results from active inhibition. Responses are concentration dependent between 0.25% and 2.5%, plateau from 2.5% to 5%, and can decline at higher concentrations. Formalin also results in tissue edema, and this is longer lasting. Responses to formalin up to 2.5% are predominantly neurogenic, while at higher concentrations, responses involve a further prominent inflammatory component. Within the spinal cord, formalin increases c-Fos expression in neurons and causes activation of microglia, and these may contribute more prominently to longer term changes. Acute responses (to 90 min) may represent a model of ongoing acute pain involving inflammation and aspects of central sensitization, while longer term responses (days, weeks) may represent a model of changes involved in persistent pathological pain.
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