Current status of opiate receptors and their agonists is reviewed--basic aspects of receptor theo... more Current status of opiate receptors and their agonists is reviewed--basic aspects of receptor theory, the importance of stereospecificity in drug-receptor interactions and the role of 'second messengers' in drug action. The three classes of endogenous opioids, originating from three distinct genes, are discussed: pro-opiomelanocortin, giving rise to beta-endorphin, ACTH and various MSHs; pro-enkephalin, giving methionine enkephalin and leucine enkephalin; and prodynorphin; their anatomical distribution and the main classes of receptors with which they interact, the mu-receptor, with a high affinity for met-enkephalin and beta-endorphin (as well as morphine and dynorphin A); the delta-receptor for which the primary ligand is leu-enkephalin; and the kappa-receptor which is the main target for the dynorphins. Functional roles for endogenous opioids are considered. Essentially they are inhibitory to target neurones, depressing motor reflexes, baroreflexes and nociception. They also have roles in the response to physical and psychological stress.
In six suburban areas of Sydney, chosen to provide a socioeconomic cross-section of the city, com... more In six suburban areas of Sydney, chosen to provide a socioeconomic cross-section of the city, complete records of dispensing of benzodiazepine were collected over a four-week period. These drugs constituted 3.7% of all dispensing, female patients outnumbered males by 2.3:1, and 98% of patients were over 20 years of age. The predominance of females, and higher age groups was found in all the areas studied, but no socioeconomic correlation was detected in the use of the drugs. Analysis of national dispensing figures confirmed the higher consumption in higher age groups, and revealed no heterogeneity in per capita prescribing rates amongst the States.
Oxygen toxicity was assessed in mice exposed to 5 ATA of oxygen. Central nervous system toxicity ... more Oxygen toxicity was assessed in mice exposed to 5 ATA of oxygen. Central nervous system toxicity was measured as the latent period before convulsions, and lung damage estimated by wet and dry weight measurements. Our results confirmed previous findings that hyperbaric oxygen induces hypothermia in animals, and this effect is profound in mice exposed to 5 ATA of oxygen at ambient temperatures of 15 degrees C and 5 degrees C. However, even marked hypothermia had very little effect on the latent times to convulsions in mice. Unexpectedly, the combination of hypothermia and hyperbaric oxygen produced much more severe lung damage than either treatment alone, with a 2.7-fold increase in weight in the 5 degrees C group (average rectal temperature of 16.1 degrees C). These results indicate that hyperoxic-induced hypothermia cannot be considered a protective mechanism against oxygen toxicity and indeed hypothermia can markedly potentiate hyperbaric oxygen toxicity.
ABSTRACT Noel Butlin radically altered the debate about the pre-colonial Aboriginal population wh... more ABSTRACT Noel Butlin radically altered the debate about the pre-colonial Aboriginal population when he provided a set of hypothetical demographic scenarios, which nonetheless were both grounded in economic theory or human ecological considerations and broadly consistent with what we know about the historical record. This research builds on Butlin's legacy by exploring how his scenarios are consistent with both the medical understandings of the infectiousness and mortality of various diseases and the history of settlement. Another contribution from this paper is to highlight the possible role of chickenpox in the Aboriginal depopulation in the early colonial period.
The challenge to achieve a gestalt understanding of general anaesthesia is really dependent upon ... more The challenge to achieve a gestalt understanding of general anaesthesia is really dependent upon an understanding of the elusive concept of consciousness. Until very recently, anaesthesia has been understood to depend fundamentally on the lipid solubility of anaesthetic agents, unsurprisingly a misleading view which has followed from the greater simplicity of lipid chemistry compared with protein chemistry and, it is contended here, from a serious misunderstanding of the older experimental data. Nonetheless, because an over-simplistic view of lipids pertains in much pharmacological thinking about anaesthesia, this paper devotes some attention to potentially relevant aspects of lipid function and also to concepts of anaesthesia which are based on the properties of intracellular and extracellular water. It is argued that the more correct pharmacological explanation is likely to be action at hydrophobic sites of crucial functional molecules, most plausibly protein molecules: empirical data which support such actions are presented and considered. Anaesthetic actions on a range of such proteins are discussed, with the emphasis on general neurophysiological principles, with the intent of avoiding the mire into which detailed consideration of actions at specific sites of putative function in the central nervous system can lead. Those experimentally-documented actions include influences on the proteins which constitute the Na(+)-ion conductance channels in axonal membranes (which are the basis for action potentials); on the Ca(2+)-ion channels which are crucial for neurotransmitter secretion from nerve terminals; on the properties of the ion channels in the post-synaptic membranes of the neurons which are the targets for transmitter action; on components of the "second messenger" systems of target neurons; as well as actions on metabolically significant enzymes (notably cytochrome P450). The overall argument is that the concept of anaesthetic actions on lipids should be abandoned in favour of one which is consistent with the general pharmacological principle of drug action at specific receptor sites, i.e. a targeted action at unique loci on relevant proteins.
The Journal of pharmacology and experimental therapeutics, 2000
The higher incidence of inflammatory and painful disorders in women and recent reports that have ... more The higher incidence of inflammatory and painful disorders in women and recent reports that have emphasized the importance of gender in nociceptive sensitivity and responsiveness to analgesics prompted us to investigate gender as a factor in the variability in response to opioids. We studied the anti-inflammatory and antinociceptive effects of two kappa-opioid agonists in adjuvant-induced arthritis, one that acts both peripherally and centrally (PNU50488H; 20 mg/kg/day), the other which is peripherally selective (asimadoline; 5 mg/kg/day). Both drugs had equally powerful anti-inflammatory effects in both male and female rats (reducing measures by 60-80%). In contrast, there were gender-based heterogeneities in their analgesic actions, contingent on the method of stimulation (mechanical or thermal); males were insensitive to the analgesic effects of asimadoline with thermal but not mechanical nociceptive stimuli. We also sought evidence for gender influences on the joint content of S...
The Journal of pharmacology and experimental therapeutics, 2000
Possible contributions of the hypothalamo-hypophyseal-adrenal axis to the development of adjuvant... more Possible contributions of the hypothalamo-hypophyseal-adrenal axis to the development of adjuvant-induced arthritis and therapeutic actions of the prototypical kappa-opioid agonist PNU-50,488H (PNU-50) were studied in DA rats. Paw edema, nociception, histological and radiological joint damage, and tumor necrosis factor-alpha release by peritoneal macrophages were measured in adrenalectomized (ADX) and sham-operated (SHO) arthritic animals (drug-treated and untreated groups). Disease developed earlier in ADX rats (paw edema was first apparent 11 days postadjuvant compared with day 13 in SHO animals) and remained more severe in that group. Twice-daily PNU-50 treatment completely prevented the development of edema in the SHO group but was effective in the ADX animals only on day 18. PNU-50 substantially reduced the pooled severity index (combined quantitative edema, histological and radiological assessments) at day 18 in both SHO and ADX rats and to an equal extent. During disease deve...
... Damian Grace 1 & John Carmody 2. ... Sir. Your editorial "Hollow apologies should be... more ... Damian Grace 1 & John Carmody 2. ... Sir. Your editorial "Hollow apologies should be avoided" (Nature 403, 813; 2000) noted that Hubert Markl, president of the Max Planck Society (MPS), "is right to resist pressure to apologize" for the participation of German scientists in Nazi ...
Current status of opiate receptors and their agonists is reviewed--basic aspects of receptor theo... more Current status of opiate receptors and their agonists is reviewed--basic aspects of receptor theory, the importance of stereospecificity in drug-receptor interactions and the role of 'second messengers' in drug action. The three classes of endogenous opioids, originating from three distinct genes, are discussed: pro-opiomelanocortin, giving rise to beta-endorphin, ACTH and various MSHs; pro-enkephalin, giving methionine enkephalin and leucine enkephalin; and prodynorphin; their anatomical distribution and the main classes of receptors with which they interact, the mu-receptor, with a high affinity for met-enkephalin and beta-endorphin (as well as morphine and dynorphin A); the delta-receptor for which the primary ligand is leu-enkephalin; and the kappa-receptor which is the main target for the dynorphins. Functional roles for endogenous opioids are considered. Essentially they are inhibitory to target neurones, depressing motor reflexes, baroreflexes and nociception. They also have roles in the response to physical and psychological stress.
In six suburban areas of Sydney, chosen to provide a socioeconomic cross-section of the city, com... more In six suburban areas of Sydney, chosen to provide a socioeconomic cross-section of the city, complete records of dispensing of benzodiazepine were collected over a four-week period. These drugs constituted 3.7% of all dispensing, female patients outnumbered males by 2.3:1, and 98% of patients were over 20 years of age. The predominance of females, and higher age groups was found in all the areas studied, but no socioeconomic correlation was detected in the use of the drugs. Analysis of national dispensing figures confirmed the higher consumption in higher age groups, and revealed no heterogeneity in per capita prescribing rates amongst the States.
Oxygen toxicity was assessed in mice exposed to 5 ATA of oxygen. Central nervous system toxicity ... more Oxygen toxicity was assessed in mice exposed to 5 ATA of oxygen. Central nervous system toxicity was measured as the latent period before convulsions, and lung damage estimated by wet and dry weight measurements. Our results confirmed previous findings that hyperbaric oxygen induces hypothermia in animals, and this effect is profound in mice exposed to 5 ATA of oxygen at ambient temperatures of 15 degrees C and 5 degrees C. However, even marked hypothermia had very little effect on the latent times to convulsions in mice. Unexpectedly, the combination of hypothermia and hyperbaric oxygen produced much more severe lung damage than either treatment alone, with a 2.7-fold increase in weight in the 5 degrees C group (average rectal temperature of 16.1 degrees C). These results indicate that hyperoxic-induced hypothermia cannot be considered a protective mechanism against oxygen toxicity and indeed hypothermia can markedly potentiate hyperbaric oxygen toxicity.
ABSTRACT Noel Butlin radically altered the debate about the pre-colonial Aboriginal population wh... more ABSTRACT Noel Butlin radically altered the debate about the pre-colonial Aboriginal population when he provided a set of hypothetical demographic scenarios, which nonetheless were both grounded in economic theory or human ecological considerations and broadly consistent with what we know about the historical record. This research builds on Butlin's legacy by exploring how his scenarios are consistent with both the medical understandings of the infectiousness and mortality of various diseases and the history of settlement. Another contribution from this paper is to highlight the possible role of chickenpox in the Aboriginal depopulation in the early colonial period.
The challenge to achieve a gestalt understanding of general anaesthesia is really dependent upon ... more The challenge to achieve a gestalt understanding of general anaesthesia is really dependent upon an understanding of the elusive concept of consciousness. Until very recently, anaesthesia has been understood to depend fundamentally on the lipid solubility of anaesthetic agents, unsurprisingly a misleading view which has followed from the greater simplicity of lipid chemistry compared with protein chemistry and, it is contended here, from a serious misunderstanding of the older experimental data. Nonetheless, because an over-simplistic view of lipids pertains in much pharmacological thinking about anaesthesia, this paper devotes some attention to potentially relevant aspects of lipid function and also to concepts of anaesthesia which are based on the properties of intracellular and extracellular water. It is argued that the more correct pharmacological explanation is likely to be action at hydrophobic sites of crucial functional molecules, most plausibly protein molecules: empirical data which support such actions are presented and considered. Anaesthetic actions on a range of such proteins are discussed, with the emphasis on general neurophysiological principles, with the intent of avoiding the mire into which detailed consideration of actions at specific sites of putative function in the central nervous system can lead. Those experimentally-documented actions include influences on the proteins which constitute the Na(+)-ion conductance channels in axonal membranes (which are the basis for action potentials); on the Ca(2+)-ion channels which are crucial for neurotransmitter secretion from nerve terminals; on the properties of the ion channels in the post-synaptic membranes of the neurons which are the targets for transmitter action; on components of the "second messenger" systems of target neurons; as well as actions on metabolically significant enzymes (notably cytochrome P450). The overall argument is that the concept of anaesthetic actions on lipids should be abandoned in favour of one which is consistent with the general pharmacological principle of drug action at specific receptor sites, i.e. a targeted action at unique loci on relevant proteins.
The Journal of pharmacology and experimental therapeutics, 2000
The higher incidence of inflammatory and painful disorders in women and recent reports that have ... more The higher incidence of inflammatory and painful disorders in women and recent reports that have emphasized the importance of gender in nociceptive sensitivity and responsiveness to analgesics prompted us to investigate gender as a factor in the variability in response to opioids. We studied the anti-inflammatory and antinociceptive effects of two kappa-opioid agonists in adjuvant-induced arthritis, one that acts both peripherally and centrally (PNU50488H; 20 mg/kg/day), the other which is peripherally selective (asimadoline; 5 mg/kg/day). Both drugs had equally powerful anti-inflammatory effects in both male and female rats (reducing measures by 60-80%). In contrast, there were gender-based heterogeneities in their analgesic actions, contingent on the method of stimulation (mechanical or thermal); males were insensitive to the analgesic effects of asimadoline with thermal but not mechanical nociceptive stimuli. We also sought evidence for gender influences on the joint content of S...
The Journal of pharmacology and experimental therapeutics, 2000
Possible contributions of the hypothalamo-hypophyseal-adrenal axis to the development of adjuvant... more Possible contributions of the hypothalamo-hypophyseal-adrenal axis to the development of adjuvant-induced arthritis and therapeutic actions of the prototypical kappa-opioid agonist PNU-50,488H (PNU-50) were studied in DA rats. Paw edema, nociception, histological and radiological joint damage, and tumor necrosis factor-alpha release by peritoneal macrophages were measured in adrenalectomized (ADX) and sham-operated (SHO) arthritic animals (drug-treated and untreated groups). Disease developed earlier in ADX rats (paw edema was first apparent 11 days postadjuvant compared with day 13 in SHO animals) and remained more severe in that group. Twice-daily PNU-50 treatment completely prevented the development of edema in the SHO group but was effective in the ADX animals only on day 18. PNU-50 substantially reduced the pooled severity index (combined quantitative edema, histological and radiological assessments) at day 18 in both SHO and ADX rats and to an equal extent. During disease deve...
... Damian Grace 1 & John Carmody 2. ... Sir. Your editorial "Hollow apologies should be... more ... Damian Grace 1 & John Carmody 2. ... Sir. Your editorial "Hollow apologies should be avoided" (Nature 403, 813; 2000) noted that Hubert Markl, president of the Max Planck Society (MPS), "is right to resist pressure to apologize" for the participation of German scientists in Nazi ...
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