Normal and radiculopathic cutaneous pain tolerance levels evaluated by heat-beam dolorimetry.

The heat-beam dolorimeter has previously been used to obtain cutaneous pain tolerance measures in normal volunteers and patients with chronic pain. In the present study, normal reference data were collected at two stimulus intensities for 24 volunteers, and the stimulus-effect relationship (decreasing tolerance latency with increasing stimulus intensity) was found significant (p less than 0.001) for all body sites tested. No overall sex differences were found; males behaved slightly more stoically than females, with differences significant only at the T3 site over the breasts. At the second evaluation at the higher stimulus intensity, females exhibited lower pain tolerance (greater pain sensitivity) at the right breast than males (p less than 0.05). No significant lateral asymmetry was found in cutaneous pain tolerance except at the dorsum of the hand: the right hand evinced elevated pain tolerance compared with the left hand in both right- and left-handed subjects. Eight radiculopathic pain patients with clinically involved left L5 nerve roots were evaluated and their responses were compared with the volunteer normal reference data. The radiculopathic group evinced elevated tolerance levels in both the radiculopathic dermatome and noninvolved sites compared with normal individuals (p less than 0.05).

Role of dialysable solutes in the mediation of uremic encephalopathy in the rat.

This study addresses mechanisms of the clinical, encephalopathic uremic illness and its suppression by dialysis. Renoprival rats were treated with peritoneal dialysis (8 exchanges per day, 30 min dwell), or untreated (attrition group), and their EEG's were automatically sampled overnight and subjected to power spectrum analysis as an index of encephalopathy. As in man the background rhythm of the quantified EEG (Q.EEG) in the attrition group slowed with time as extracellular fluid composition became increasingly abnormal; these changes were normalized by therapeutic dialysis (TD) using standard, commercial dialysate. However, Q.EEG slowing was only partially normalized by solute-specific dialysis using "mock uremic dialysate" (M-UD), prepared from laboratory chemicals to equal plasma concentrations in preterminal uremic rats of urea, creatinine, potassium, phosphorus, calcium, magnesium, bicarbonate, sodium, and chloride. When only phosphate was added to TD, the Q.EEG slowed to the same level achieved after M-UD. We conclude that uremic encephalopathy in this model is produced by an unknown neurotoxin and augmented by one or more of the M-UD solutes, phosphate being a likely candidate. To localize the encephalopathic effect, regional brain glucose uptake was estimated in 20 discrete brain areas. Significance of reduced uptake in three areas is discussed.

Peak B endorphin concentration in cerebrospinal fluid: reduced in chronic pain patients and increased during the placebo response.

The level of an endogenous opioid (peak B endorphin) was measured in chromatographically fractionated cerebrospinal fluid (CSF) sampled from two groups of chronic pain patients before and after intrathecal saline (placebo) injection. As assessed by a verbal rating scale, one group reported no change in their level of pain (non-responders, NR; n = 6) while the other group reported complete or greater than 50% pain relief (placebo responders, PR; n = 14). We find, as has been reported previously, that initial peak B levels were lower (by 50%) in these chronic pain patients' CSF than in CSF from pain-free (PF) normal controls (P less than 0.001, t-test). Peak B levels measured from CSF of the NR group undergoing this procedure did not change (P greater than 0.4, paired t-test). In contrast, a significant 2.3-fold increase was measured in the CSF peak B level of the PR group (P less than 0.05, paired t-test). This is the first direct evidence that a CSF opioid is correlated with placebo pain relief in chronic pain patients. Peak B is a potent analgesic substance when administered by the intracerebroventricular route in mice and its level is related to the patients' pain status in a presumably causal manner.

Separate and combined effects of morphine and amphetamine on quantitative electroencephalogram and regional cerebral glucose uptake in a rat model.

The effects of morphine (5 mg/kg) and amphetamine (5 mg/kg) were examined on relative regional cerebral glucose uptake (RrCGlu), surveyed in 20 brain areas in the rat. No relationship was found between drug effects on the cortical RrCGlu and the quantitative electroencephalogram (QEEG) measured from frontal and occipitoparietal cortices. Discriminant function analysis revealed that the two drugs produced identifiably different QEEG changes and that the combination engendered an unique metastate that most closely resembled amphetamine's effect with no morphine characteristics. The two drugs evoked qualitatively similar RrCGlu changes at most sites surveyed, with certain exceptions which are discussed. Both increased RrCGlu at the substantia nigra. Morphine, but not amphetamine, increased RrCGlu at the periaquaeductal gray. Since amphetamine is known to potentiate morphine analgesia and to ameliorate many of the opiate's depressant effects, the finding that the combination evokes cortical QEEG changes that more closely resemble amphetamine may have implications for understanding the increased psychotoxicity of chronic combined abuse.

Comparison of the effects of central and peripheral aluminum administration on regional 2-deoxy-D-glucose incorporation in the rat brain.

Intracerebroventricular (ICV) Injection of aluminum tartrate (ALT 205.7 mcg) in the rat induces a progressive encephalopathy characterized by neurobehavioral derangements, by the slowing of the background rhythm of the quantitative electroencephalogram and by learning and memory deficits. The condition, lethal within about 35 days, is associated with a reduced ability of cerebral synaptosomes to incorporate radiolabeled 2-Deoxy-D-glucose (2DG) in vitro. The present study surveyed and compared the in vivo regional cerebral glucose uptake (rCGlu) capacity of rats injected with ALT 7 or 14 days previously either by the ICV or intraperitoneal (120 mg/Kg) routes. ICV injection produces transient rCGlu depression in caudate-putamen, geniculate bodies and periaquaeductal gray, resolving by day 14. Thalamic nuclei exhibit depressed rCGlu by the 7th day undergoing further depression by day 14. The rCGlu of occipitoparietal cortices, normal at day 7, was increased by day 14. In contrast, peripheral aluminum administration produced transient rCGlu depression in olfactory bulbs, frontal and occipitoparietal cortices, nucleus accumbens and cerebellum, and transiently increased rCGlu in the geniculate nuclei. These effects, present by day 7, had resolved by day 14 when rCGlu had increased in the previously normal pontine nuclei and decreased in the previously normal hippocampus. Neither treatment changed rCGlu in the septal nuclei, globus pallidus, amygdala, olfactory cortex, substantia nigra, superior or inferior colliculi or the medullary nuclei. The pattern of anomalies in cerebral 2DG incorporation most probably indexes the deranged glucoregulatory and metabolic demands of these brain areas in the aluminum intoxicated state.

Juvenile hypocalcemia provokes persistent electroencephalographic change in renally compromised rats.

In view of the putative involvement of calcium in uremic encephalopathy and the critical importance of this element in juvenile development, we examined the effect of temporary restriction of dietary calcium intake on serum chemistry and the quantitative electroencephalogram (Q.EEG) in unilaterally 3/4 nephrectomized juvenile male Sprague-Dawley rats. Animals were renally infarcted at 22-26 days of age (50-74 g) and placed on one of two isocaloric dietary regimens: powdered normal rat diet (ND, n = 25) or low calcium diet (LCD, n = 8) for 30 days. At this time, ND animals showed normal serum chemistries, whereas LCD rats were hypocalcemic and azotemic with significantly elevated blood urea nitrogen (BUN) and serum creatinine concentrations and reduced renal creatinine clearance values. All animals thereafter received ND for 25-34 further days, during which time chronic Q.EEG electrodes were implanted. At the end of the common ND feeding period, serum chemistry values were equal and normal in both groups. The average theta/alpha ratio (TAR) of the overnight Q.EEG was assessed for 3 days. We found that the TAR of previously LCD animals was significantly elevated compared with ND rats. This indicates an encephalopathic slowing of the background rhythm of these animals. We conclude that, following restoration of a transient uremic and hypocalcemic episode induced by LCD feeding, the Q.EEG background frequency of juvenile renally impaired rats was abnormally slow after 30 days of ND feeding.

Aluminum induced encephalopathy in the rat.

Aluminum tartrate (AlT) but not sodium tartrate (NaT) produces a progressive encephalopathy when injected intracerebroventricularly in the rat. This syndrome, lethal within 30-35 days, is characterized by progressively deranged behavior. An early startle reaction (day 14), later joined by locomotor discoordination (day 19) is followed by locomotor and electrocorticographic (ECoG) seizures (day 21) in chronically instrumented AlT rats. There is early dissociation between ECoG and locomotor aspects. When tested in the shuttlebox for estimation of learning and memory function 7-8 days after AlT injection, marked impairment of both active and passive avoidance was observed. Glucose uptake capacity of synaptosomes from brain areas of AlT and NaT animals was indexed by the 2-deoxy-D-glucose method. Striatal and cortical synaptosomes showed reduced uptake activity 7 days following AlT injection. By day 14, hypothalamic areas also became affected, striatal uptake was further inhibited, and cortical uptake was reduced to 57% of control. The ECoG background rhythm remained unchanged until days 20-23, when the mean peak frequency was reduced. The model may be useful in the study of central aluminum toxicity and may have predictive validity in the testing of procedures to counter aluminum-associated encephalopathies in man.

Partial characterization of a novel endogenous opioid in human cerebrospinal fluid.

Human cerebrospinal fluid (CSF) contains many uncharacterized endogenous opioids, in addition to the known enkephalins, endorphins, and dynorphins. These opioids may be separated by gel filtration chromatography and identified by radioreceptor assay for opioid activity. One region of the chromatographic elution profile, designated "Peak B" has previously been shown to be related to the pain status of chronic pain patients. We now report that human Peak B isolated from the CSF of pain-free elective surgery patients is present at a typical concentration equivalent in activity to 1.4 pmol of morphine sulfate per ml of CSF measured by radioreceptor assay. At a dose of 0.06 and 0.12 pmol morphine sulfate equivalents of CSF (MSE), injected into the cerebroventricular system of the mouse, Peak B produced an antinociceptive effect, the intensity and duration of which was dose-dependent and which was antagonized by naloxone. The mouse vas deferens (MVD) preparation was inhibited by Peak B in a manner that was sensitive to antagonism by naloxone only at low (less than 1.0 microM) but not at higher (greater than 6.0 microM) concentrations of the antagonist. Peak B activity in the MVD assay was unaffected by treatment with trypsin or alpha-chymotrypsin.

Local analgesia without anesthesia using peripheral perineural morphine injections.

Twenty-five patients with chronic pain were treated with nerve blocks. They were divided into two groups, A and B, according to the volume of local anesthetic required for surgical anesthesia by standard nerve block techniques. The 16 patients in group A had pain in the distribution of small nerves, which could be blocked with 5 ml or less. They were blocked in a random, double-blind crossover fashion using 0.5% bupivacaine or 0.02% morphine. The nine patients in group B were injected simultaneously with saline, 30 ml perineurally and 1 ml intramuscularly. Morphine (6 mg) was added, in a random, double-blind fashion, to one of the injections. A second pair of injections was subsequently done, using morphine by the alternative route. Perineural morphine provided statistically longer lasting pain relief than did either intramuscular morphine or perineural bupivacaine.

Studies of aluminum in rat brain.

The effects of high aluminum concentrations in rat brain were studied using(14)C autoradiography to measure the uptake of [(14)C]2deoxy-D-glucose ([(14)C]2DG) and microbeam proteon-induced X-ray emission (microPIXE) with a 20-µm resolution to measure concentrations of magnesium, aluminum, potassium, and calcium. The aluminum was introduced intracisternally in the form of aluminum tartrate (Al-T), and control animals were given sodium tartrate (Na-T). The(14)C was administered intravenously. The animals receiving Al-T developed seizure disorders and had pathological changes, which included cerebral cortical atrophy. The results showed that there was a decreased uptake of [(14)C]2DG in cortical regions in which increased aluminum levels were measured, i.e., there was a correlation between the aluminum in the rat brain and decreased brain glucose metabolism. A minimum detection limit of about 16 ppm (mass fraction) or 3×10(9) Al atoms was obtained for Al under the conditions employed.

Staphylococcal alpha toxin induced changes in the electroencephalogram of the rat.

Staphylococcal alpha-toxin at 1 microgram and 10 micrograms was injected into the right lateral ventricle of the brain of conscious, unrestrained rats. Clinical behavior and changes in EEG patterns were monitored. Clinical behavior attributed to alpha-toxin intoxication consisted of intermittent periods of stretching, tremors, convulsions and 'barrel rolling'. The EEG patterns, selected from recordings obtained during quiescent periods of behavior, demonstrate focal spiking, with and without recruitment, slow waves, spindling and complex spikes. We conclude that the central nervous system is a critical target for the lethal action of alpha-toxin.

Morphine tolerance is associated with elevated levels of an uncharacterized endorphin (peak B) in mouse brain with no change in 3H-dihydromorphine binding.

A partially characterized mouse brain endorphin was shown to be elevated (p 0.01 U-Test) in ICR strain mice that had been made tolerant but not dependent upon morphine (5 mg/kg sc., given for 32 days). The animals were tolerant to the antinociceptive effect of morphine as judged by the tail immersion assay (48 degrees C) but showed no detectable dependence or withdrawal syndrome effects following the administration of naloxone (writhing, jumping, diarrhea or hypermotility) on day 33. No significant changes were seen in any other mouse brain endorphins (p 0.05 U-Test). Also there was no apparent change in the number of binding properties of 3H-dihydromorphine (3H-DHM) receptors (mu-receptors) in chronic morphine (CM) treated, as compared with chronic saline (CS) treated animals.

Rapid intracerebroventricular injection assisted by an automatic syringe.

Rapid intracerebroventricular (icv) injections in the conscious mouse are described, using a small volume gas-tight syringe with repeating dispenser device (Hamilton Bonadoz, Switzerland). The device gives reproducibility within 2% of chosen volume, while facilitating rapid icv injections to groups of animals. The technique is used to demonstrate in the mouse the antinociceptive activity of clonidine, using the tail-immersion test.

A comparison of muscarinic cholinergic involvement in the antinociceptive effects of morphine and clonidine in the mouse.

The antinociceptive effects (AE) of morphine and clonidine were examined in the mouse tail immersion test (48 degrees C). The interactions of these two agents with cholinergic (muscarinic) and anticholinergic (antimuscarinic) drugs were examined with respect to antinociceptive effect. Physostigmine, administered peripherally and intracerebroventricularly (i.c.v.) increased the AE of both morphine and clonidine. Atropine sulphate (but not atropine methylnitrate) antagonized the AE of both morphine and clonidine in a dose-dependent manner. Oxotremorine (OTMN) produced an AE that was additive with that of morphine and clonidine without being synergistic. These findings are discussed in terms of possible cholinergic mechanisms involved in the AEs produced by morpine and clonidine.