Trends in mortality from aortic dissection analyzed from the World Health Organization Mortality Database from 2000 to 2017.

BACKGROUND: We assessed trends in aortic dissection (AD) death rates in 23 countries from 2000 to 2017. METHODS: We extracted AD mortality data for countries with high usability data from the World Health Organization (WHO) Mortality Database and from the Center for Disease Control (CDC) WONDER Database for the United States of America (USA). Age Standardized Death Rates (ASDRs) per 100,000 population were computed. Trends were assessed by locally weighted scatter plot smoother (LOWESS) regression. RESULTS: Between 2000 and 2017, ASDRs from AD decreased in Australia, Belgium, Croatia, Denmark, France, Italy, New Zealand, Norway, Sweden, the United Kingdom, and the USA for both sexes. Increasing AD mortality was observed in Austria, Czech Republic, Germany, Hungary, Israel, and Japan for both sexes. The largest absolute increases in ASDR were in Japan for men (+1.59) and women (+1.11). The largest percentage decreases were in Norway for men (-0.91) and in New Zealand (-0.6) for women. In 2017, the highest mortality rates were in Japan for both sexes (3.22 and 2.09, respectively). The lowest ASDR was in Kyrgyzstan for both sexes (0.16 and 0.10, respectively). ASDRs for AD in 2017 were higher for men than women in all countries included. Spain had the greatest difference between the gender's mortality rates with a 2.71-fold higher mortality average rate in men. CONCLUSION: We identified an overall decrease in AD mortality in most included countries, while an increase was noted in other countries including Israel and Japan.

Mortality from abdominal aortic aneurysm: trends in European Union 15+ countries from 1990 to 2017.

BACKGROUND: This observational study assessed trends in abdominal aortic aneurysm (AAA) death rates in European Union (EU) 15+ countries for the years 1990 to 2017. METHODS: Age-standardized death rates (ASDRs) were extracted from the Global Burden of Disease Study Global Health Data Exchange. Trends were analysed using joinpoint regression analysis. RESULTS: Between 1990 and 2017, ASDRs from AAA decreased in all 19 EU15+ countries for women, and in 18 of 19 countries for men. Increasing AAA mortality was observed only for men in Greece (+5·3 per cent). The largest relative decreases in ASDR between 1990 and 2017 were observed in Australia (men -65·6 per cent, women -50·4 per cent) and Canada (men -60·8 per cent, women -48·6 per cent). Over the 28-year interval, the smallest decreases in ASDR for women were noted in Greece (-2·3 per cent) and in Italy (-2·5 per cent). In 2017, the highest mortality rates were observed in the UK for both men and women (7·5 per 100 000 and 3·7 per 100 000 respectively). The lowest ASDR was observed in Portugal for men (2·8 per 100 000) and in Spain for women (1·0 per 100 000). ASDRs for AAA in 2017 were higher for men than women in all 19 EU15+ countries. The most recent trends demonstrated increasing AAA ASDRs in 14 of 19 countries for both sexes; the increases were relatively small compared with the improvements in the preceding years. CONCLUSION: This observational study identified decreasing mortality from AAA across EU15+ countries since 1990. The most recent trends demonstrated relatively small increases in AAA mortality across the majority of EU15+ countries since 2012.

ANTECEDENTES: Este estudio observacional evalúa las tendencias en las tasas de mortalidad del aneurisma de aorta abdominal (abdominal aortic aneurysm, AAA) en los 19 países integrantes del acrónimo conocido como EU15+ en los aóos 1990-2017. MÉTODOS: Se obtuvieron las tasas de mortalidad estandarizadas por la edad del Global Burden of Disease Study Global Health Data Exchange. Las tendencias se analizaron utilizando el análisis de regresión por puntos de inflexión (joinpoint). RESULTADOS: Entre 1990 y 2017, las tasas de muerte estandarizadas por edad (age-standardized death rates, ASDR) del AAA disminuyeron en todos los 19 EU15+ países para las mujeres, y en 18 de los 19 países para los varones. Solamente se observó un incremento de la mortalidad del AAA para los varones en Grecia (+5,3%). El mayor descenso relativo de ASDR entre 1990-2017 se observó en Australia (varones -65,6%, mujeres -50,4%) y Canadá (varones -60,8%, mujeres -48,6%). A lo largo del periodo de 28 aóos, en el caso de las mujeres, los menores descensos en ASDR se observaron en Grecia (-2,3%) y en Italia (-2,5%). En 2017, las tasas de mortalidad más elevadas se observaron en el Reino Unido tanto para varones como para mujeres (7,5/100.000 y 3,7/100.000 para varones y mujeres, respectivamente). La ASDR más baja se observó en Portugal para varones (2,8/100.000) y Espaóa para mujeres (1,0/100.000). Las ASDRs para AAA en 2017 fueron más altas para varones que para mujeres en todos los 19 países EU15+. Las tendencias más recientes demostraron aumentos de las ASDRs por AAA en 14 de 19 países para varones y mujeres; los aumentos fueron relativamente pequeóos cuando se compararon con las mejorías observadas dentro de los aóos precedentes. CONCLUSIÓN: En este estudio observacional de los países EU15+, se ha identificado una disminución en la mortalidad de los AAA entre los países integrantes de EU15+ desde 1990. Las tendencias más recientes demuestran aumentos relativamente pequeóos de la mortalidad del AAA en la mayoría de los países EU15+ desde 2012.

Trends in malignant melanoma mortality in 31 countries from 1985 to 2015.

BACKGROUND: Malignant melanoma (MM) causes the highest absolute number of deaths among skin cancers. An up-to-date analysis of international MM mortality trends is required for assessing the burden of disease, and may support the assessment of the effectiveness of new diagnostic, therapeutic and preventative strategies. OBJECTIVES: To report MM mortality trends between 1985 and 2015 using the World Health Organization (WHO) Mortality Database. MATERIALS AND METHODS: We used country-level MM mortality data from the WHO Mortality Database for all countries with high usability death registration data. Mortality trends were described using Joinpoint regression modelling. RESULTS: Thirty-one countries met the inclusion criteria. All countries, except the Czech Republic, demonstrated increased age-standardized death rates (ASDRs) in males over the observation period. More countries exhibited decreased or stable MM mortality in females. The median mortality rate for 2013-2015 was 2·57 deaths per 100 000 for males and 1·55 per 100 000 for females. Australia and Norway had the highest ASDRs for males (5·72 per 100 000 and 4·55 per 100 000, respectively). Norway and Slovenia had the highest ASDRs for females (3·02 per 100 000 and 2·58 per 100 000, respectively). MM mortality was greater for males than females in all countries, with sex disparity increasing across the period. Disparity in mortality between older and younger cohorts in several countries was also found. CONCLUSIONS: An overall increase in MM mortality over the past 30 years was observed. However, there was notable variation in mortality trends between countries, as well as between males and females, and between different age groups.

New species of Simona Moulds, 2012 and Chelapsalta Moulds, 2012 cicadas (Cicadidae: Cicadettinae: Cicadettini) from Australia: comparative morphology, songs, behaviour and distributions.

In 2012, Moulds established the morphologically similar cicada genera Simona and Chelapsalta, each with one Australian species (sancta Distant and puer Walker, respectively). In this paper, two new species are described within the genus Simona Moulds 2012, S. erema sp. nov. and S. retracta sp. nov., and one within the genus Chelapsalta Moulds 2012, C. myoporae sp. nov. The type species of Simona (female holotype), S. sancta (Distant, 1913), is redescribed based on a contemporary male, nominated a plesiotype, held in the Australian National Insect Collection. Melampsalta subgulosa Ashton 1914 is supported as a junior synonym of S. sancta. The species within the two genera of Simona and Chelapsalta are morphologically very similar. S. erema occurs widely through the arid regions of inland Australia, extending west from western Queensland through the Northern Territory, to central-western Western Australia, a linear distance of approximately 2200 km. S. retracta is known from a single semi-arid locality in southern inland Queensland. C. myoporae occurs widely through southeast, central and southwest Queensland, extending southwards into inland and western N.S.W. and southeastern South Australia. It tends to occur most commonly within vegetation associated with seasonal riverine floodplains, and in some areas of poorly drained and clay-rich soils. The calling songs of these three species, together with those of S. sancta and C. puer, are described. Detailed comparisons made of the songs of S. erema and C. myoporae, each from three widely separated locations, clearly exhibit structural consistency in their calling songs across their distributions. The Simona songs are complex and contain multiple elements; the species are very mobile and wary, and inhabit low dense shrubland. The songs of the two Chelapsalta species, both relatively sedentary in behaviour, in contrast consist of relatively uniform chirping and buzzing elements. It is suggested that, although the two genera are morphologically similar, the calling songs, behaviour and habitats do distinguish them, at least as represented by these species documented. MaxEnt modeling of the species climatic envelope for the widely distributed species Simona erema suggests an association with summer-peak rainfall and diurnal temperature range. Modeling under estimated conditions of the Last Glacial Maximum (22 ky) suggests the possibility of an even more widespread distribution at that time.

Subcutaneously administered Repronex in oligoovulatory female patients undergoing ovulation induction is as effective and well tolerated as intramuscular human menopausal gonadotropin treatment.

OBJECTIVE: To determine the efficacy and safety of Repronex SC as compared with Repronex IM and Pergonal IM in patients undergoing ovulation induction. DESIGN: Randomized, open-label, multicenter, parallel group study. SETTING: Ten academic and private fertility clinics with expertise in ovualtion induction. PATIENT(S): Premenopausal anovulatory and oligoovulatory females (n = 115) undergoing ovulation induction. INTERVENTION(S): Down-regulation with leuprolide acetate followed by up to 12 days of treatment with gonadotropins and hCG administration and luteal phase progesterone support. MAIN OUTCOME MEASURE(S): Percentage of patients ovulating; percentage of cycles with follicular development meeting criteria for hCG administration; number of follicles recruited per cycle meeting hCG criteria; peak serum E(2) levels; rates of chemical, clinical and ongoing pregnancies; adverse events; injection-site pain scores. RESULT(S): There was no statistically significant difference in the percentage of women who ovulated among the treatment groups. However, Repronex SC was significantly more effective than Pergonal IM in producing follicular development in patients who met hCG criteria. There were no significant differences in clinical, ongoing, or continuing pregnancy rates or in multiple pregnancies among the treatment groups. No differences were found in the safety assessments, proportions or seriousness of adverse events or treatment discontinuations. Also, there were no differences between the three treatment groups in patient-recorded scores of injection-site pain or injection-site reactions. CONCLUSION(S): Repronex SC is as efficacious and well tolerated as Repronex IM or Pergonal IM in ovulation induction. Self-administration of Repronex SC provides a convenient treatment alternative to daily IM injections.

Allochronic speciation, secondary contact, and reproductive character displacement in periodical cicadas (Hemiptera: Magicicada spp.): genetic, morphological, and behavioural evidence.

Periodical cicadas have proven useful in testing a variety of ecological and evolutionary hypotheses because of their unusual life history, extraordinary abundance, and wide geographical range. Periodical cicadas provide the best examples of synchronous periodicity and predator satiation in the animal kingdom, and are excellent illustrations of habitat partitioning (by the three morphologically distinct species groups), incipient species (the year classes or broods), and cryptic species (a newly discovered 13-year species, Magicicada neotredecim). They are particularly useful for exploring questions regarding speciation via temporal isolation, or allochronic speciation. Recently, data were presented that provided strong support for an instance of allochronic speciation by life-cycle switching. This speciation event resulted in the formation of a new 13-year species from a 17-year species and led to secondary contact between two formerly separated lineages, one represented by the new 13-year cicadas (and their 17-year ancestors), and the other represented by the pre-existing 13-year cicadas. Allozyme frequency data, mitochondrial DNA (mtDNA), and abdominal colour were shown to be correlated genetic markers supporting the life-cycle switching/allochronic speciation hypothesis. In addition, a striking pattern of reproductive character displacement in male call pitch and female pitch preference between the two 13-year species was discovered. In this paper we report a strong association between calling song pitch and mtDNA haplotype for 101 individuals from a single locality within the M. tredecim/M. neotredecim contact zone and a strong association between abdomen colour and mtDNA haplotype. We conclude by reviewing proposed mechanisms for allochronic speciation and reproductive character displacement.

Reproductive character displacement and speciation in periodical cicadas, with description of new species, 13-year Magicicada neotredecem.

Acoustic mate-attracting signals of related sympatric, synchronic species are always distinguishable, but those of related allopatric species sometimes are not, thus suggesting that such signals may evolve to "reinforce" premating species isolation when similar species become sympatric. This hypothesis predicts divergences restricted to regions of sympatry in partially overlapping species, but such "reproductive character displacement" has rarely been confirmed. We report such a case in the acoustic signals of a previously unrecognized 13-year periodical cicada species, Magicicada neotredecim, described here as a new species (see Appendix). Where M. neotredecim overlaps M. tredecim in the central United States, the dominant male call pitch (frequency) of M. neotredecim increases from approximately 1.4 kHz to 1.7 kHz, whereas that of M. tredecim remains comparatively stable. The average preferences of female M. neotredecim for call pitch show a similar geographic pattern, changing with the call pitch of conspecific males. Magicicada neotredecim differs from 13-year M. tredecim in abdomen coloration, mitochondrial DNA, and call pitch, but is not consistently distinguishable from 17-year M. septendecim; thus, like other Magicicada species, M. neotredecim appears most closely related to a geographically adjacent counterpart with the alternative life cycle. Speciation in Magicicada may be facilitated by life-cycle changes that create temporal isolation, and reinforcement could play a role by fostering divergence in premating signals prior to speciation. We present two theories of Magicicada speciation by life-cycle evolution: "nurse-brood facilitation" and "life-cycle canalization."

Three approaches to use of questioning by clinical lecturers: a pilot study.

In the current health care climate nurses require very good problem solving and critical thinking skills. Questioning as a teaching strategy is viewed as one way to promote such student learning. Using a comparative descriptive quantitative and a qualitative approach, this pilot study investigated the types of questions asked of students by lecturers working within the preceptorship model in the clinical setting. A convenience sample of five volunteer nursing lecturers were tape recorded during their interactions with undergraduate students (n = 8). Initially two auditing approaches were used to analyse the interview data: relevant parts of Mogan and Warbinek's (1994) Observation of Nursing Teachers in Clinical Settings instrument (ONTICS Tool) and Craig and Page's (1981) conceptual framework as adapted by Sellappah, Hussey, Blackmore and McMurray (1998). The data were further analysed by qualitative content analysis. This study supported the findings of the ONTICS tool and Sellappah et al's framework that teachers asked predominantly directive style and low level questions. What the two approaches did not adequately capture was the complexity of the lecturers' questioning behaviours or the effects of contextual factors. The content analysis process however, identified three broad categories forming a model that effectively integrated aspects of the context of the lecturer/student interaction. It also represented lecturer questioning behaviours more comprehensively. The preliminary model offered has the potential to highlight the importance of lecturers asking questions that lead students to extend their thinking about practice. It could also contribute to student learning by assisting lecturers to understand the value and critical nature of their questioning and serve as a framework for staff development.

Platelets and DAMI megakaryocytes possess beta-secretase-like activity.

We report here the discovery of two novel human platelet and megakaryocytic DAMI cell enzymes that have beta-secretase-like activity. These activities could potentially effect cleavage of the amyloid precursor protein (APP) at the beta-amyloid peptide N-terminus, by an EC 3.4.24.15-like metalloprotease, and the N terminus-1 position, by a serine protease. Thus both enzymes may generate the amyloidogenic beta-peptide. Studies of intact and Triton X-100-lysed DAMI cells, as well as intact versus subcellular fractions of platelets, demonstrate the presence of these proteolytic activities. The resting platelet has (1) a surface serine protease, demonstrated by its ability to cleave a beta-secretase substrate and by its inhibitor sensitivity; and (2) a metalloprotease, recognized by an antibody to EC 3.4.24.15, which resides intracellularly in the alpha-granule membrane, is translocated to the surface on activation, and shows beta-secretase-like activity by cleaving the same substrate. This metalloprotease can also cleave recombinant APP to a potentially amyloidogenic fragment. Surface metalloprotease was identified in DAMI cells by flow cytometry and Western blotting with a specific anti-EC 3.4.24.15 monoclonal antibody, while activity was identified by using two beta-secretase substrates. This article is the first to document two previously unknown endoproteinases with beta-secretase-like activity in platelets and DAMI cells. These proteases are capable of effecting cleavage of APP and could therefore contribute to Abeta deposition in the cerebrovasculature.

Blood brain barrier endothelial cells express candidate amyloid precursor protein-cleaving secretases.

Proteolytic cleavage of the amyloid precursor protein (A beta PP) results in the generation of the amyloidogenic fragment known as amyloid beta peptide (A beta). Deposition of A beta in the brain parenchyma and cerebrovasculature is a feature of Alzheimer's disease (AD). To date, the process whereby A beta is generated and deposited remains unclear. We have previously established that activated platelets from AD patients retain more A beta PP on their surface than control platelets. We report here that an endothelial cell-derived enzyme can cleave this surface platelet A beta PP. Human blood brain barrier endothelial cells from brains of AD patients were assayed for potential A beta PP-cleaving enzymes using synthetic peptide substrates encompassing the A beta N-terminus cleavage site. A protease activity capable of cleaving A beta PP on the surface of AD platelets was noted. The A beta PP cleavage is partially inhibited by EDTA, by ZincOV, as well as by a specific inhibitor of the Zn metalloprotease E.C.3.4.24.15. Furthermore, the protease is recognized by an antibody directed against it, using immunohistochemistry, Western blot analysis and flow cytometry. The protease is not secreted, but rather resides intracellularly as well as on the surface of the endothelial cells. The data suggest that E.C.3.4.24.15 synthesized by brain endothelial cells may process the platelet-derived A beta PP, yielding fragments which could contribute to cerebrovascular A beta deposits.

Induction of matrix metalloproteinase-2 in human immunodeficiency virus-1 glycoprotein 120 transgenic mouse brains.

Human immunodeficiency virus (HIV)-1 can invade the brain and cause degeneration of the central nervous system, resulting in a host of cognitive and motor impairments. HIV-1 glycoprotein 120 (gp120), has been implicated in the neurodegenerative effects of HIV infection. Here, gp120's neurotoxic potential is demonstrated in both transgenic mice and cultured cells. We observed that gp120 causes an induction of matrix metalloproteinase (MMP)-2 activity and protein in transgenic mouse brains and in transfected C6 cells. We propose that induced MMP-2 may contribute to a neurodegenerative environment by degrading extracellular matrix (ECM) fibronectin and type IV collagen.

Identification of a novel serine protease-like molecule in human brain.

Proteolysis of the amyloid beta protein precursor (APP) is a key event in the development of Alzheimer's disease. In our search for proteases that can cleave APP and liberate the amino terminus of the amyloidogenic beta protein, we characterized a calcium-dependent serine protease (CASP) which is present in reactive astrocytes and cross-reacts with anti-cathepsin G antibodies. We wanted to take advantage of this cross-reactivity to clone the cDNA of CASP and eventually evaluate its tissue distribution. Screening of two human fetal brain cDNA libraries with anti-cathepsin G antibodies led to the identification of a cDNA coding for a novel protein whose only homology to known proteins is to the active site of trypsin-type serine proteases. We called this protein the novel serine protease (NSP). NSP exists in at least three differentially spliced forms, one of which is expressed predominantly in brain and testis. Immunohistochemistry and immunoprecipitation with antibodies generated against NSP show that it is expressed and secreted by a variety of cells and that, in brain, it is found primarily in cerebrovascular smooth muscle cells and reactive astrocytes.

Synthesis and secretion of active alpha 1-antichymotrypsin by murine primary astrocytes.

Activated astrocytes have been identified as the main source of the serine protease inhibitor alpha 1-antichymotrypsin (ACT), an acute phase protein that is tightly associated with amyloid plaques in Alzheimer's disease (AD) and in normal aged human and monkey brain. We analyzed the synthesis of ACT by cultured murine astrocytes in vitro. The murine astrocytes expressed an ACT-like antigen that crossreacted with antibodies to human ACT. The murine ACT-like protein is secreted by the astrocytes and is able to form an SDS-resistant complex with the serine protease cathepsin G, indicating that the secreted ACT is biologically active. We conclude that cultured primary astrocytes synthesize and secrete murine ACT in an active form. We, therefore, suggest that the ACT present within AD plaques is locally derived from plaque-associated activated astrocytes as a part of a glia-mediated local inflammatory response that is associated with the neurodegeneration seen in AD.

Cardiotonic agents. 6. Histamine analogues as potential cardiovascular selective H2 agonists.

Twenty-six alkyl and aralkyl histamine analogues were prepared as potential cardiotonic agents. Compounds were designed to allow interaction with a putative secondary aryl binding site at the H2 receptor, the presence of which was inferred from the structure of cyprohepatadine, which is known to have H2-antagonist properties. The compounds were examined for inotropic activity in ferret papillary muscle. Potent inotropic activity was generally found in N-alkyl- and N,N-dialkylimidazole-4-ethanamines, whereas N-(amidoalkyl)imidazole-4-ethanamines and N-alkylimidazole-4-propanamines were at best weakly active. Five compounds were examined in screens designed to assess hemodynamic effects and gastric acid secretion in vivo. Two of these compounds, alpha-(3-phenyl-2-transpropenyl)-1H-imidazole-4-ethanamine and N-heptyl-1H-imidazole-4-ethanamine, showed positive inotropic activity with minimal effects on heart rate and mean arterial pressure in vivo; however, both compounds were found to stimulate gastric acid secretion. These results demonstrate that selectivity between various H2-receptor-mediated activities can be obtained with substituted histamine analogues.

Cholinergic false transmitters: physiological and biochemical actions in central and peripheral systems.

Three N-ethyl substituted analogs of acetylcholine (ACh) were evaluated for potential use as false neurotransmitters to decrease cholinergic transmission. This evaluation included (1) the elevation of arterial blood pressure upon central administration, (2) depression of blood pressure upon intravenous injection and (3) interactions with central muscarinic and peripheral nicotinic receptors. With respect to the central pressor response, ACh, acetylmonoethylcholine (AMECh) and acetyldiethylcholine (ADECh) were full agonists of decreasing potency; acetyltriethylcholine (ATECh) was a partial agonist of considerably lower potency. The duration of response paralleled potency. With respect to the peripheral depressor response, ACh and AMECh were full agonists of equal potency, and ADECh and ATECh were partial agonists of at least 100-fold lower potency. In terms of their affinity for central muscarinic receptors (brainstem and cerebral cortex), the following series was obtained: ACh greater than AMECh much greater than ADECh = ATECh. All of the agents had a greater affinity for muscarinic receptors in the brainstem compared to cortex. Acetylcholine and AMECh recognized multiple receptor binding conformations; the binding of ADECh and ATECh indicated interaction with a single set of equivalent sites. The affinity for nicotinic ACh receptors from the Torpedo electric organ was ACh = AMECh much greater than ADECh; ATECh had little affinity for these receptors. Acetylcholine, AMECh and ADECh stimulated the binding of [3H]phencyclidine to the ion channel of nicotinic receptor (potency series = ACh greater than AMECh = ADECh); ATECh was inactive. Acetylcholine, AMECh and ADECh also induced receptor conversion to a desensitized conformation; ATECh did not.(ABSTRACT TRUNCATED AT 250 WORDS)

Group C Niemann-Pick disease: faulty regulation of low-density lipoprotein uptake and cholesterol storage in cultured fibroblasts.

Incubation of mutant Niemann-Pick C fibroblasts with low-density lipoprotein (LDL) resulted in excessive internalization of lipoprotein and extensive cellular over-accumulation of unesterified cholesterol. The uptake of LDL by the mutant cells appeared to occur through the classic LDL receptor pathway and internalized lipoprotein was processed in lysosomes. Lipoprotein uptake into mutant cells was associated with delays in the initiation of established cellular cholesterol homeostatic responses. Subcellular fractionation of mutant Niemann-Pick C fibroblasts accumulating LDL-cholesterol showed excess unesterified sterol to be localized in the light lysosome-light membrane region of a Percoll gradient, and revealed that cholesterol storage was associated with a specific alteration in the normal profiles of lysosomal marker enzymes.

Spinal cholinergic neurons and the expression of morphine withdrawal symptoms in the rat.

Behavioral and autonomic signs of the morphine withdrawal syndrome were measured in dependent rats injected with the opiate antagonist naloxone. The purpose of this study was to determine whether spinal cholinergic pathways play a role in the expression of spinally mediated withdrawal symptoms. Intrathecal (i.t.) administration of 1 microgram carbachol or 5 micrograms neostigmine resulted in increases in mean arterial pressure (MAP) of 32 and 45 mm Hg, respectively, in conscious, freely moving rats. The pressor response to carbachol began almost immediately after injection, but that to neostigmine was delayed in onset. Both responses were completely abolished following i.v. injection of 2 mg/kg atropine. However, in spinal-transected (C-1), ventilated rats, i.t. injection of carbachol or neostigmine resulted in only small, transient increases in MAP. Intraarterial (i.a.) injection of 0.5 mg/kg naloxone to morphine-dependent rats resulted in an immediate increase in MAP (to 33 mm Hg) that lasted at least 1 hr. This was accompanied by classical behavioral signs of withdrawal. Pretreatment of dependent rats with i.t. injection of atropine or hemicholinium-3 (HC-3) significantly reduced the pressor and several behavioral responses elicited by naloxone. In contrast, when morphine-dependent, spinal-transected rats were pretreated with i.t. injection of cholinergic antagonists, i.a. injection of naloxone resulted in an enhanced MAP response. Finally, in intact dependent rats, i.t. injection of naloxone (6 micrograms) produced a 14 mm Hg increase in MAP that was significantly augmented (21 mm Hg) following i.t. pretreatment with HC-3.(ABSTRACT TRUNCATED AT 250 WORDS)

Spontaneous morphine withdrawal from the rat spinal cord.

A characteristic and reproducible sign of narcotic withdrawal is the naloxone induced increase in arterial pressure. In morphine-dependent rats allowed to undergo spontaneous withdrawal (6-24 h) and then transected at the spinal C-1 level, arterial pressure was maintained at a significantly higher level than either spinal-transected nondependent controls or morphine-dependent, spinal-transected rats pithed from C-1 to L-4. These findings indicate that the morphine-dependent spinal cord, independent of supraspinal influences, is able to exhibit an autonomic component of spontaneous withdrawal.

Dorsal root lesions block the expression of morphine withdrawal elicited from the rat spinal cord.

Evidence has been accumulating to indicate that the spinal cord plays an important role in the expression of several narcotic abstinence signs in the intact animal. One characteristic and reproducible withdrawal sign which can be elicited in both intact and spinal-transected dependent rats is the naloxone-induced increase in arterial blood pressure. Employing this model, this autonomic component of narcotic withdrawal was quantitated in dependent spinal (C1)-transected rats with intact dorsal roots and in those with surgical lesions of the dorsal roots from T3 to L4. The withdrawal-associated hypertension observed in animals with intact dorsal roots was abolished in the rats having the lesioned roots. The central spinal location of the opiate receptors mediating the naloxone response was confirmed by experiments demonstrating the failure of a selective peripherally acting narcotic antagonist to elicit a comparable withdrawal response. It was concluded that continuous afferent input and spinal opiate receptors are requirements for the expression of spinal narcotic withdrawal.