Oral opioids for chronic non-cancer pain: higher prevalence of hypogonadism in men than in women.

The effect of chronic oral opioids on hypothalamus-pituitary-gonadal axis in women, and on bone mineral density (BMD) in men and women is not known. The objective of this cross-sectional study was to determine the effect of long-term oral opioids on gonadal status and BMD in male and female patients with chronic non-cancer pain (CNCP). We included 26 community-dwelling CNCP patients, 12 men and 14 premenopausal women, treated with oral opioids for at least one year. We obtained Visual Analogue Scale for pain score, BMD and plasma LH and FSH in all patients; menstrual history and estradiol in women; free androgen index and total and free testosterone in men. Men were older then women (p<0.05) and had used opioids for a longer period (7.2+/-3.8 and 4.1+/-1.8 years, respectively; p<0.05), but there was no difference in opioid dose or pain score between sexes. The prevalence of hypogonadism was high in men (75%), while only 21% of the women reported oligo- or amenorrhea indicating hypogonadism (P<0.01, between sexes). Osteopenia was found in 50% of men and 21% of women (p=NS). We conclude that in CNCP patients receiving chronic opioid therapy there is a much higher prevalence of hypogonadism in men then in women. This needs to be considered clinical practice.

Quantification of pain-induced changes in cerebral blood flow by perfusion MRI.

The purpose of this study was to assess if the functional activation caused by painful stimuli could be detected with arterial spin labeling (ASL), which is a non-invasive magnetic resonance imaging (MRI) technique for measuring cerebral blood flow (CBF). Because ASL directly measures blood flow, it is well suited to pain conditions that are difficult to assess with current functional MRI, such as chronic pain. However, the use of ASL in neuroimaging has been hampered by its low sensitivity. Recent improvements in MRI technology, namely increased magnetic field strengths and phased array receiver coils, should enable ASL to measure the small changes in CBF associated with pain. In this study, healthy volunteers underwent two ASL imaging sessions, during which a painful thermal stimulus was applied to the left hand. The results demonstrated that the ASL technique measured changes in regional CBF in brain regions that have been previously identified with pain perception. These included bilateral CBF changes in the insula, secondary somatosensory, and cingulate cortices, as well as the supplementary motor area (SMA). Also observed were contralateral primary somatosensory and ipsilateral thalamic CBF changes. The average change in CBF for all regions of interest was 3.68ml/100g/min, ranging from 2.97ml/100g/min in ipsilateral thalamus to 4.91ml/100g/min in contralateral insula. The average resting global CBF was 54+/-9.7ml/100g/min, and there was no change in global CBF due to the noxious thermal stimulus.

Neuroanatomical and pharmacological assessment of Fos expression induced in the rat brain by the phosphodiesterase-4 inhibitor 6-(4-pyridylmethyl)-8-(3-nitrophenyl) quinoline.

A major obstacle in the therapeutic development of phosphodiesterase-4 (PDE4) inhibitors is the production of adverse side effects such as nausea and vomiting. Immunohistochemical detection of Fos-like immunoreactivity (FLI) was used to address the neuroanatomical basis for the pharmacological actions of PDE4 inhibitors. The potent and selective PDE4 inhibitors 6-(4-pyridylmethyl)-8-(3-nitrophenyl) quinoline (PMNPQ) and rolipram elevated FLI in brain regions potentially relevant to the anti-depressant and emetic effects of PDE4 inhibition. PMNPQ and rolipram elevated FLI in the locus coeruleus, habenula, paraventricular nucleus of the thalamus, amygdala and nucleus accumbens, all structures with strong limbic connectivity implicated in arousal, memory and affective aspects of behaviour. Consistent with the emetic effects of PDE4 inhibitors such as PMNPQ and rolipram, these compounds elevated FLI in caudal brainstem nuclei such as the area postrema and nucleus of the solitary tract. Administration of the NK(1) antagonist RP 67580 prior to PMNPQ reversed increases in FLI produced by PMNPQ in these regions. RP 67580 did not, however, reduce PMNPQ-induced FLI in limbic structures. These findings suggest that PDE4 inhibitors produce emesis by increasing NK(1) receptor activation in the AP/NTS and implicate brain regions associated with reward and mood such as the amygdala, paraventricular nucleus of the thalamus, habenula and nucleus accumbens in the anti-depressant activity of such compounds.

Effects of fimbria-fornix transection on calpain and choline acetyl transferase activities in the septohippocampal pathway.

The ability of fimbria-fornix bilateral axotomy to elicit calpain and caspase-3 activation in the rat septohippocampal pathway was determined using antibodies that selectively recognize either calpain- or caspase-cleaved products of the cytoskeletal protein alphaII-spectrin. Radioenzymatically determined choline acetyl transferase (ChAT) activity was elevated in the septum at day 5, but reduced in the dorsal hippocampus at days 3, 5 and 7, after axotomy. Prominent accumulation of calpain-, but not caspase-3-, cleaved spectrin proteolytic fragments was observed in both the septum and dorsal hippocampus 1-7 days after axotomy. ChAT-positive neuronal cell bodies in the septum also displayed calpain-cleaved spectrin indicating that calpain activation occurred in cholinergic septal neurons as a consequence of transection of the septohippocampal pathway. Calpain-cleaved alphaII-spectrin immunoreactivity was observed in cholinergic fibers coursing through the fimbria-fornix, but not in pyramidal neurons of the dorsal hippocampus, suggesting that degenerating cholinergic nerve terminals were the source of calpain activity in the dorsal hippocampus following axotomy. Accumulation of calpain-cleaved spectrin proteolytic fragments in the dorsal hippocampus and septum at day 5 after axotomy was reduced by i.c.v. administration of two calpain inhibitors. Calpain inhibition partially reduced the elevation of ChAT activity in the septum produced by transection but failed to decrease the loss of ChAT activity in the dorsal hippocampus following axotomy. These findings suggest that calpain activation contributes to the cholinergic cell body response and hippocampal axonal cytoskeletal degradation produced by transection of the septohippocampal pathway.

Seizure onset times for rats receiving systemic lithium and pilocarpine: sources of variability.

Injection of 30 mg/kg of pilocarpine 24 h after systemic injection of lithium (3 mEq/kg) results in overt limbic motor seizures within about 30 min. Results of several experiments indicated that whereas food deprivation or repeated nociceptive stimulation during the previous 24 h decreased seizure onset times (SOTs) by about 11 to 12 min, food restriction, continuous lighting, or, handling during the previous 7 to 14 days increased SOTs by comparable durations. Early handling before weaning but not injections of clomimpramine also decreased SOTs. A difference of 18 min in the means of SOTs was produced by injecting either 1.0 (increased SOT) or 1.5 mg/kg (decreased SOT) of dexamethasome during the previous 24 h. A strong (multiple r=.87) association between SOTs and the amount of damage within five specific thalamic-limbic nuclei was observed. These results, in conjunction with blood corticosterone levels taken before and after induction of the seizures, suggest the neurochemical mechanisms affecting the range in SOTs could involve the adrenocorticotropic hormone (ACTH)-corticosterone system and influence the amount of post-seizure-induced damage.

Synergistic induction of severe hypothermia (poikilothermia) by limbic seizures, acepromazine and physical restraint: role of noradrenergic alpha-1 receptors.

The maintained production of extreme reductions in core temperature (20-22 degrees C) or poikilothermia can be reliably produced by the synergistic interaction of limbic seizures (induced by lithium and pilocarpine), postseizure administration of a single injection of acepromazine, and physical restraint. Administration of the specific and nonspecific dopamine antagonists haloperidol, chlorpromazine, SCH23390, or clozapine did not simulate the effect at clinically effective dosages. Single injections of phentolamine and prazosin but not of propranolol instead of acepromazine following the seizures produced the poikilothermia. This effect was also reproduced by reducing the amount of the rats' adipose weight before the induction of the seizures and physical restraint. Rats that had been restrained or not restrained and displayed either euthermia or hypothermia exhibited significantly different patterns in brain damage within limbic and thalamic structures.

Kindling modulates the IL-1beta system, TNF-alpha, TGF-beta1, and neuropeptide mRNAs in specific brain regions.

Cytokines and neuropeptides may be involved in seizure-associated processes. Following amygdala kindling in rats, we determined alterations of IL-1beta, IL-1 receptor antagonist (IL-1Ra), IL-1 receptor type I (IL-1RI), IL-1 receptor accessory proteins (IL-1R AcPs) I and II, TNF-alpha, TGF-beta1, neuropeptide Y (NPY), glycoprotein 130 (gp 130) and pro-opiomelanocortin (POMC) mRNA levels in the parietal, prefrontal and piriform cortices, amygdala, hippocampus and hypothalamus. Messenger RNAs expression in all brain regions was determined 2 h or 3 weeks following the last generalized convulsive seizure triggered from the ipsilateral kindled amygdala. The same brain region sample was used to assay for changes of all mRNA components. The results show that the 2 h-kindled group exhibited a significant up-regulation of IL-1beta, IL-1RI, TNF-alpha and TGF-beta1 mRNAs in all three cortical brain regions, amygdala and hippocampus. The largest up-regulation occurred in the prefrontal cortex (about 30-fold induction for IL-1beta and TNF-alpha mRNAs). IL-1R AcP I and II mRNA levels were also up-regulated in the cortical regions. No changes in IL-1beta, IL-1RI or TNF-alpha mRNA levels occurred in the 3 week-kindled group. NPY mRNA levels increased in the hippocampus, prefrontal and piriform cortices in the 2 h-kindled group, while IL-1Ra, gp 130, or POMC mRNA levels did not change in any group. The overall profile of mRNA changes shows specificity of transcriptional modulation induced by amygdala kindling. The data support a role of cytokines and NPY in the adaptive mechanisms associated with generalized seizure activity, with implications for neuroprotection, neuronal dysfunction and vulnerability associated with epileptic activity.

Attenuation of ischemia-induced cellular and behavioral deficits by X chromosome-linked inhibitor of apoptosis protein overexpression in the rat hippocampus.

Transient forebrain ischemia produced by four-vessel occlusion (4-VO) triggers the delayed death of CA1 neurons in the hippocampus, resulting in behavioral deficits of spatial learning performance. We demonstrate that CA1 neuronal loss induced by 4-VO (12 min) is preceded by a selective and marked elevation of catalytically active caspase-3 in these neurons, indicative of apoptosis. Virally mediated overexpression of the anti-apoptotic gene X chromosome-linked inhibitor of apoptosis protein (XIAP) prevented both the production of catalytically active caspase-3 and degeneration of CA1 neurons after transient forebrain ischemia. CA1 neurons protected in this manner appeared to function normally, as assessed by immunohistochemical detection of the neuronal activity marker nerve growth factor inducible-A and by spatial learning performance in the Morris water maze. These findings indicate that caspase-3 activation is a key event in ischemic neuronal death and that blockade of this event by XIAP overexpression permits CA1 neurons to survive and operate properly after an ischemic insult.

Emergent properties following brain injury: the claustrum as a major component of a pathway that influences nociceptive thresholds to foot shock in rats.

Flinch (pain) thresholds for electric current delivered to the feet were correlated with the amount of necrosis within the diencephalon and telencephalon for rats in which seizures had been induced by lithium and pilocarpine about two months before the testing. The shared variance of the quantitative damage within the claustrum, the anterior part of the paraventricular nucleus of thalamus, (central) mediodorsal thalamus, and lateral amygdala (ventromedial part) explained 81% of the variance in the nociceptive (flinch) thresholds. A primary role of the claustrum within the neuropathways that mediate the response to the interoceptive and "painful" characteristics of stimuli is indicated. The concept of primary pathways versus "emergent" pathways subsequent to excitotoxic damage within the neuromatrix is discussed.

Effect of enhanced geomagnetic activity on hypothermia and mortality in rats.

The hypothesis was investigated that variability in the severity of limbic seizure-induced hypothermia in rats was affected by ambient geomagnetic activity. Data were obtained in support of this hypothesis. The depth of the hypothermia was significantly (P < 0.001) reduced if the ambient geomagnetic activity exceeded 35 nT to 40 nT. Mortality during the subsequent 5 days was increased when the geomagnetic activity was > 20 nT. The magnitude of the effect was comparable to the difference between exposure to light or to darkness during the 20 h after the induction of limbic seizures.

Decreased latencies for limbic seizures induced in rats by lithium-pilocarpine occur when daily average geomagnetic activity exceeds 20 nanoTesla.

A decrease in the latency for the overt display of limbic seizures following the systemic injection of lithium and pilocarpine is weakly associated with enhanced global geomagnetic activity (in nanoTesla; nT). To determine the optimal threshold in global geomagnetic activity that is required for this effect, the seizure onset times for over 300 rats were dichotomized according to successive 5 nT increments. The results suggested that the seizure process occurred about 12% more quickly when the average daily global geomagnetic activity exceeded 20-25 nT and is commensurate with the observations by other researchers.

Dissociation between conditioned taste aversion and radial maze learning following seizure-induced multifocal brain damage: quantitative tests of serial vs. parallel circuit models of memory.

Multivariate analyses between conditioned taste aversion (CTA) and radial maze acquisition (RMA) scores and percentages of neuronal dropout within thalamic and telencephalic structures were completed for rats in which overt seizures had been evoked following a single systemic injection of lithium/pilocarpine. Despite multifocal damage, only the amount of damage within the hippocampus (CA1) and the basolateral amygdala was most strongly associated with attenuated CTA, whereas damage within the mediodorsal thalamus was primarily associated with RMA. There was no significant correlation between CTA or RMA. Multiple regression analyses for specific Paxinos and Watson structures and their traditional aggregates supported more precise delineation of neuronal substrates of learning/memory and a multimodal (parallel) model for these processes.

The sensed presence as right hemispheric intrusions into the left hemispheric awareness of self: an illustrative case study.

The hypothesis of vectorial hemisphericity predicts that left hemispheric intrusions of the right hemispheric equivalent of the sense of self should be associated with the experience of a "presence" of someone else. The neurophenomenological profile of a woman whose medical history satisfied these theoretical criteria (verified electrical anomalies that could encourage phasic discharges within the right temporal lobe and atrophy within the left temporoparietal region) is presented. In addition to interactions between electrical seizures and thinking, she reported a long history of sensed presences, ego-alien intrusions, and "sudden knowing of the subsequent sequences of seizures" before they occurred clinically. The existence of these neurocognitive processes demands a reevaluation of the psychiatric default explanations of "hysteria" and questions the belief that "awareness during seizures" or "premonition of subsequent somatosensory experience" contraindicates an epileptic process.

Concordance of quantitative damage within the diencephalon and telencephalon following systemic pilocarpine (380 mg/kg) or lithium (3 mEq/kg)/pilocarpine (30 mg/kg) induced seizures.

We tested the hypothesis that a single systemic injection of 380 mg/kg of the muscarinic agonist pilocarpine would produce more diffuse and severe seizure-induced brain damage than a single injection of lithium (3 mEq/kg) followed 4 h later by < 1/10 the dosage of pilocarpine. The hypothesis was not supported; the pattern of quantitative brain damage 50-60 days after the seizures were elicited by either treatment was comparable within the limits of measurement error. Within the diencephalon and subcortical telencephalon the same structures were either damaged in a similar quantitative manner or were spared. Only five of the 119 damaged structures exhibited statistically significant treatment differences at P < 0.01. The results are compatible with the explanation that lithium may enhance the excitotoxic effects of subsequent muscarinic stimulation.

Prevention of sudden cardiac death by the atypical neuroleptic acepromazine following status epilepticus in rats.

Normal male rats in which status epilepticus has been induced by injecting 30 mg/kg of pilocarpine after a single systemic administration of lithium (sufficient to produce blood levels of 0.2 mEq/L) invariably die within 24 hr. Real-time monitoring indicated sudden cardiac death; it was preceded by progressive intensification of arrhythmia. A single systemic injection (25 mg/kg) of the atypical phenothiazine acepromazine prevented the mortality and virtually eliminated the cardiac instability.

Accompanying the dying patient--the doctor's role.

Yvon Bureau, president of the "Responsable jusqu'à la fin" foundation, spoke at the annual congress of the Quebec section of the College of Family Physicians of Canada. A social worker, Bureau spoke as if he were a doctor and asked some important questions as to what would be his relationship to his patient. His insights can be applied to anyone who works with those who are dying or terminally ill.

Behaviors of rats with insidious, multifocal brain damage induced by seizures following single peripheral injections of lithium and pilocarpine.

Several domains of behavior were measured in rats (n = 465) 10 days to 100 days after induction of limbic seizures by a single subcutaneous injection of lithium and pilocarpine. These rats displayed enhanced intragroup aggression but normal muricide; gustatory neophobia and conditioned taste aversion were virtually eliminated. Severe working and reference memory deficits were evident within the radial arm maze. Both state-dependent memory and possible situation-dependent precipitation of spontaneous seizures were suggested. The behavioral changes were considered commensurate with the multifocal pattern of thalamic, hippocampal/amygdaloid, and limbic cortical damage.

Prenatal diagnosis of trisomy 9 mosaic presenting as a case of Dandy-Walker malformation.

Trisomy 9 syndrome is a rare chromosomal anomaly associated with specific patterns of multisystem dysmorphism and occasional central nervous system (CNS) malformations, the most common being the Dandy-Walker malformation. Milder anomalies are usually seen with trisomy 9 mosaicism. We report what we believe to be the first case of a baby with an isolated Dandy-Walker malformation which was diagnosed prenatally and was subsequently found to have a trisomy 9 mosaic syndrome.

Extreme hypothermia induced by a synergism of acute limbic seizures, physical restraint, and acepromazine: implications for survival following brain injury.

Core temperature was measured in rats 24 hr. after they had been assigned to one of 8 groups in a 3-way analysis of variance design that involved (1) induction of limbic seizures by a systemic injection of lithium/pilocarpine, (2) physical restraint, and (3) administration of acepromazine. An extraordinarily powerful interaction was noted among seizures, physical restraint, and acepromazine-produced hypothermia (24 degrees C) compared to the other 7 treatments (> 35 degrees C). The putative poikilothermic response is commensurate with the loss of mammalian behaviors that follow these seizures. Implications for survival during the acute stages of brain injury are suggested.

Transient blocking of persistent gnawing by haloperidol in rats with seizure-induced multifocal brain damage.

Frequent but phasic gnawing of objects is displayed by rats in which severe damage within: 1) the substantia nigra reticulata, 2) all of the amygdaloid nuclei except the central group and 3) multiple thalamic nuclei, was induced by lithium/pilocarpine-induced seizures. Multiple lesions were produced by these rats upon their own tails as well as upon the tails of their cage mates. These behaviors were considered predictable sequela of the disinhibition of compacta dopamine upon orofacial mechanisms that are modulated by the corpus striatum. In a manner similar to tail pinch-induced eating, the usually quick onset of spontaneous gnawing upon food chunks in a test setting was delayed transiently by appropriate dosages of haloperidol.