Differential activity of selective opioid agonists on hypothalamic magnocellular neuronal activity.
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3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Biomedical subjects
D M Wright
Publications and source records attributed to D M Wright.
Repeated hemoperfusion and continuous arteriovenous hemofiltration in a paraquat poisoned patient.
Prompt hemodialysis or hemoperfusion can be of value during the first 24 hours after paraquat ingestion particularly when the patient has developed acute renal failure. However, many cases of paraquat poisoning occur in areas where hemoperfusion facilities are unavailable. In contrast, continuous arteriovenous hemofiltration (CAVH) could be instituted easily. We have measured the removal of paraquat from the body by CAVH in a 46 year old male cane farmer who ingested 70 ml, 20% paraquat and died twelve days later from pulmonary fibrosis. Renal failure developed rapidly. Concentrations of paraquat were measured by an indirect competitive ELISA using a murine paraquat monoclonal IgG antibody. Hemoperfusion was performed daily for five days, beginning 78 hours post-ingestion. By 180 hours, when the patient was in respiratory failure, hemoperfusion was replaced with CAVH which was continued for 46 hours. During this time interval, 1.1 mg paraquat was recovered in the hemofiltrate and 1.56 mg paraquat in the urine. The extraction of paraquat by the hemofilter was close to 100%. The plasma clearance of paraquat across the hemofilter was 6.1 ml/min and the renal clearance was 8.2 ml/min. The mean hemoperfusion clearance of paraquat was 50 ml/min and the total amount of paraquat removed by the 34 hours of hemoperfusion was 9 mg. Because of the relative ease with which CAVH can be performed, its low cost, compared to that of hemoperfusion or hemodialysis, and the continuous nature of the procedure, CAVH may be worth considering in paraquat poisoning. It could be used particularly in those patients who have developed renal failure or while patients are being prepared for hemoperfusion.
Hemofiltration↗
Zinc and paired-pulse potentiation in the hippocampus.
Zinc was added to the perfusate of rat hippocampal slices to determine the effect on the potentiation of evoked responses in subfield CA3 following paired-pulse stimulation of mossy fibres. Paired-pulse potentiation across a range of interpulse intervals and currents was significantly depressed by 50 and 500 microM zinc chloride. Additionally but only at the higher concentration, the amplitude of the first evoked potential was significantly increased. These results provide further evidence of a role for zinc in hippocampal neurotransmission.
Animals↗
Effect of zinc on neuronal activity in the rat forebrain.
Zinc ions, which are unevenly distributed in the CNS and can be released from nerve terminals, have been implicated as causative agents in epileptogenesis. The present study has shown that intraventricular administration to anesthetized rats causes seizure activity of the ECOG and convulsions. Since the manner in which zinc influences neuronal activity and triggers convulsions is unclear, studies were also made of its effect on spontaneous and evoked activity in the rat forebrain. It was found that iontophoretic application of zinc to cortical neurons causes slow and often prolonged increases in firing rate, usually accompanied by bursts of high frequency discharge in just under half the studies. Another cation, barium, evoked excitatory responses of a similar type and a reduction in potassium permeability may underlie the effects of both cations. In contrast, calcium, magnesium, manganese and cerium caused short duration depressant effects. The depression induced by calcium, but not by the other cations, could be blocked by zinc. Similarly, in the hippocampus zinc depressed calcium-dependent potentiation in subfield CA3 evoked by paired-pulse stimulation of mossy fibers; excitatory effects (namely an increase in spike amplitude and appearance of multiple population spikes) were seen at higher zinc concentrations. The depressant effects of an enkephalin analog on cortical firing rate were also blocked by zinc, consistent with studies from another laboratory suggesting enkephalin/zinc interactions. In contrast, the depressant effect of GABA could not be blocked by zinc, although an antagonism has been reported in the lobster muscle. Firm conclusions regarding the mechanism(s) underlying the triggering of seizure activity by zinc cannot yet be drawn, but the results of these studies would be consistent with an interference with calcium and/or potassium ion activity rather than with GABA binding sites.
Action Potentials↗
Stress-induced analgesia evoked by intraperitoneal injection of hypertonic saline: evidence for its occurrence in vasopressin deficient rats.
Experiments were carried out to investigate whether vasopressin is involved in stress-induced analgesia. Intraperitoneal injection of hypertonic saline caused a significant and dose-related increase in the latency to the tail-flick response of the rat to noxious heat and was used as a stimulus for stress-induced analgesia. Neither the pituitary nor opioid peptides appeared to be involved, since the response occurred in hypophysectomized rats and was not reduced by the opiate antagonist naloxone. Furthermore hypertonic-saline analgesia was clearly potentiated in hypophysectomized rats in comparison to sham-operated controls. Hypertonic-saline analgesia was also observed in vasopressin-deficient (homozygous Brattleboro) rats similar in both magnitude and duration to that in normal rats of the same strain (Long Evans). It was concluded that vasopressin was not involved in stress-induced analgesia evoked by hypertonic saline.
Animals↗
Evidence for a spinal site at which opioids may act to inhibit the milk-ejection reflex.
Morphine was injected into the lumbar subarachnoid space of anaesthetized lactating rats (7-10 days post partum) to examine its effect on the milk-ejection reflex at a spinal level. Although the delay until the first milk-ejection response to the suckling of hungry pups was variable (3-60 min) the subsequent responses occurred at regular intervals of 7.5 +/- 0.4 min; milk-ejection responses were detected by measurement of intramammary pressure and by the characteristic behaviour of the pups. Injection of morphine (4-50 micrograms) via a cannula inserted into the spinal subarachnoid space inhibited reflex milk ejection in a dose-related manner without affecting the sensitivity of the mammary gland to exogenous oxytocin (1 mu., i.v.); injection extradurally was without effect. The opiate antagonist naloxone (10 micrograms), when injected intrathecally, did not significantly alter the pattern of reflex milk ejection or the amplitude of the intramammary pressure response, but prevented the inhibitory effect of morphine when administered with the opiate. Pethidine (250 and 400 micrograms) also inhibited the milk-ejection reflex. It is unlikely that the effect of spinal administration of morphine occurred as the result of the transportation to a supraspinal site since release of oxytocin evoked by intraventricular injection of hypertonic sodium chloride (3 mol/l) was blocked by intraventricular injection of morphine (4 micrograms) but not by a much larger dose (40 micrograms) injected intrathecally.
Animals↗
Zinc: effect and interaction with other cations in the cortex of the rat.
Zinc and other cations were iontophoretically applied to neurones in the frontoparietal cortex of urethane-anaesthetised rats and their effect on the activity of these cells was examined. Slow and often prolonged increases in firing rate occurred in 45.2% of neurones after zinc application and 72.7% after barium. Calcium caused short duration decreases in firing rate in 89.3% of neurones as did manganese (78.6%) cerium (21.9%) and magnesium (33.3%). When applied simultaneously zinc blocked the depressant effect of calcium (in 79.3% of neurones) but not that of manganese or GABA; other ions were ineffective. These results suggest that zinc, which is known to be present in nerve terminals, may modulate neuronal activity.
Animals↗
Inhibition of oxytocin secretion by mu and delta receptor selective enkephalin analogues.
The effects on oxytocin release of enkephalin analogues, thought to be highly selective agonists of the mu or delta opioid receptor, were compared. Oxytocin release was evoked in urethane-anaesthetised rats (7-10 days post partum) by intracerebroventricular injection of NaCl (3M) at 15-20 min. intervals and detected by the resultant increase in intramammary pressure. Enkephalin analogues (the mu receptor agonist Tyr-D-Ala-Gly-MePhe-NH (CH2)2OH (DAGO), the delta receptor agonist (D-Ala2-D-Leu5) - enkephalin (DADLE) and metkephamid, which has been reported to be particularly efficacious at the delta receptor) were administered intracerebroventricularly 3-5 min. prior to hypertonic saline. Oxytocin release was inhibited in a dose-dependent, naloxone-reversable manner by DAGO (ED50 : 40ng), DADLE (ED50 : 156ng) and metkephamid (ED50 : 42ng); the mammary gland sensitivity to oxytocin was unaffected. These results suggest that the inhibitory action may be mediated through both mu and delta receptors and provide further evidence in support of a role of enkephalins in the control of oxytocin secretion.
Animals↗
A comparison of analgesia and suppression of oxytocin release by opiates.
The potency of opiates for suppressing oxytocin release relative to their potency as analgesics was tested in lactating rats. Oxytocin release was evoked by the sucking of the young in urethane-anaesthetized and unanaesthetized rats, and was detected by the characteristic behaviour of the young and milk yield respectively. The tail-flick test, using noxious radiant heat, was used to assess analgesia. Intraperitoneal injection of morphine (1 mg kg-1 and 5 mg kg-1) significantly reduced milk yield in unanaesthetized rats. Urethane-anaesthetized rats displayed a pattern of reflex milk-ejection responses similar to that found in conscious rats. This reflex was significantly inhibited in a dose-related, naloxone-reversible manner by buprenorphine (ED50 0.18 mg kg-1), meptazinol (ED50: 14.0 mg kg-1), morphine (ED50: 0.67 mg kg-1), pentazocine (ED50: 15.0 mg kg-1) and pethidine (ED50: 7.9 mg kg-1). Although intraperitoneal injection of morphine (5 mg kg-1) abolished the increase in intramammary pressure occurring at reflex milk-ejection, that evoked by intravenous oxytocin (0.5-1 mu) was unaffected. Each opiate also caused significant, dose-related, naloxone-reversible increases in tail-flick latency. The ED50 doses were buprenorphine (ED50: 0.14 mg kg-1), meptazinol (ED50: 12.5 mg kg-1), morphine (ED50: 5.0 mg kg-1), pentazocine (ED50: 12.5 mg kg-1) and pethidine (ED50: 6.1 mg kg-1). The order of potency for analgesia and for suppression of oxytocin release were identical, namely: buprenorphine greater than morphine greater than pethidine greater than meptazinol greater than pentazocine. The results obtained with lactating rats suggest that secretion of the hormone oxytocin is substantially reduced during opiate-induced analgesia.
Analgesia↗
Effect of ACTH on opiate inhibition of oxytocin release.
beta-Endorphin (200ng), dynorphin1-17 (2 micrograms) and morphine (4 micrograms) suppressed the osmotically-evoked release of oxytocin in anaesthetized lactating rats. ACTH1-24 (0.2-3 micrograms) administered intraventricularly 3 min before beta-endorphin or morphine attenuated their inhibitory action, but when applied afterwards was never seen to reverse their effects although this was achieved with naloxone (lmg X kg-1, i.v.). ACTH however, was ineffective against dynorphin. At higher doses an opiate-like action of ACTH was observed. Thus ACTH may act as a partial antagonist and at higher doses as a partial agonist of the opiate receptor for which it is known to have an affinity. It is suggested that suppression of oxytocin release by endogenous beta-endorphin could be modified by ACTH with which it may be co-released.
Adrenocorticotropic Hormone↗
A microcomputer based system for spike processing at low cost.
A system is described for the quantification of neuronal activity utilizing a microcomputer as an alternative to a conventional hard-wired ratemeter. The system, which counts the number of action potentials occurring in successive epochs, consists of a microcomputer and a small number of external electronic components (e.g. D leads to A chips, counter chips and latches) housed together with the power supply in a subrack. Output is both digital (a video monitor is used to display the count, cumulative count and elapsed time) and analogue (a chart recorder is used to record a frequency/time histogram) for two channels. Variables such as epoch time and analogue output scaling are read in from switches via latches hung onto a data-bus and can be altered without interference with the running of the program. The program is written in BASIC and stored on a C-MOS memory chip. In comparison to alternative storage systems (i.e. cassette and floppy disk) this has the advantage of immediate access and low cost; furthermore the program is readily modified.
Animals↗
Substance P reduces tail-flick latency: implications for chronic pain syndromes.
In the awake restrained rat the intrathecal administration of substance P or the partial substance P homologue eledoisin-related peptide (ERP) reduced reaction time to a noxious radiant heat stimulus and, at high doses, produced additional behavioural responses suggesting that the animals had reacted to what they perceived as a painful stimulus. The reduction in tail-flick latency was observed as early as 30 sec following peptide administration peaked at 1 min and persisted for 5-10 min, after which an overshoot of the response (i.e., an increase in reaction time) was observed. The responses varied in their magnitude with the amount of peptide given, substance P being approximately 4 times more potent on a molar basis than ERP. Intrathecal administration of an equal volume of vehicle (artificial cerebrospinal fluid) had no effect on tail-flick latency and failed to produce any of the other behavioural changes. The following interpretations are made. The decrease in tail-flick latency suggests that pain threshold was decreased, and the dramatic behavioural effects seen at high doses suggest that an excess of substance P in the spinal cord is capable of producing a painful sensation. The rapid onset of the response suggests rapid penetration of substance P and ERP to the appropriate receptors, and the rapid decay of the response suggests rapid removal. Taken together, these results are consistent with the earlier suggestion that substance P plays a role as an excitatory agent in sensory pathways subserving pain. It is proposed that some conditions of chronic pain in man may therefore be due to an overabundant amount of substance P. This is complementary to a second proposal that other cases of chronic pain may be due to a supersensitivity of substance P receptors. The former is more likely to be associated with organic disorders, the latter with nerve damage, e.g. with causalgia, the neuralgias and perhaps some cases of phantom limb pain.
Analgesia↗
Ethyl beta-carboline-3-carboxylate antagonizes the action of GABA and benzodiazepines in the hippocampus.
In urethane-anaesthetized rats, the beta-carboline derivative beta CCE (0.3-1.0 mg/kg i.v.) excited hippocampal pyramidal cells which were inhibited by GABA (applied iontophoretically) and benzodiazepines (applied iontophoretically or intravenously). While benzodiazepines facilitated the action of GABA, the effects of GABA and benzodiazepines were antagonized by beta CCE. This electrophysiological study supports the behavioural observations that beta CCE is a benzodiazepine receptor antagonist.
Animals↗
Diurnal rhythm in sensitivity of a nociceptive spinal reflex.
To detect possible diurnal variation in the nociceptive threshold of male Wistar rats the latency between onset of noxious radiant heat and the tail-flick response was measured in day (a.m.) and night experiments. The response latency was significant (P less than 0.001) longer, i.e. the response was less sensitive, at night in both normal and spinalized rats. This is the first indication of a diurnal rhythm in the sensitivity of a spinal reflex to noxious stimulation.
Animals↗
Effects of morphine and naloxone on the responses to noxious stimulation of neurones in the nucleus reticularis paragigantocellularis.
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Animals↗
Design for an inexpensive unit for measuring tail flick latencies.
A reflex action timer for use in rat tail flick tests is described. This timer utilizes a photoelectric sensor to detect reaction times accurately. It was designed to avoid the sensing groove required in some other such units, can be used as a chronometer/controller in a number of other experimental paradigms, and can be built at low cost.
Animals↗
The effects of chronic section of dorsal roots on the responsiveness of motoneurones to 5-hydroxytryptamine and a substance P analogue.
1 Experiments were performed on rats 14-21 days after unilateral dorsal root section in order to determine if the effects on motoneurone excitability of a substance P analogue, 5-hydroxytryptamine (5-HT) and noradrenaline were altered by section of primary afferents. 2 The effects of iontophoretic applications of these agents on motoneurone excitability were quantified by measuring the change in amplitude of the short latency field potentials evoked antidromically, by ventral root stimulation. 3 Iontophoretic application of the substance P analogue (eledoisin-related peptide, ERP) always produced an increase in the amplitude of the field potential. These increases in amplitude were 25.9% larger on the sides of the cords with sectioned dorsal roots. This was not statistically significant difference (P greater than 0.05). 4 Section of dorsal roots did not alter responses to noradrenaline. 5 Responses to 5-HT were significantly larger following section of dorsal roots. There is very little evidence for the release of 5-HT by primary afferents and denervation supersensitivity is an improbable explanation. It is possible that descending 5-HT systems directly excite motoneurones and indirectly inhibit primary afferent transmission. Dorsal root section would alter the balance between these actions of 5-HT in favour of an excitatory effect.
Animals↗
Responses of spinal neurones to a substance P analogue, noxious pinch and bradykinin.
It is likely that substance P is a neurotransmitter at the first afferent synapse. These synapses may mediate pain sensations from thermal, mechanical or chemical (bradykinin) stimulation of nociceptors. Correlation of the responsiveness of dorsal horn neurones to iontophoretic application of a substance P analogue and mechanical or chemical stimulation of the hind limb suggested that sensitivity to substance P was shown by cells responding to chemical but not mechanical noxious stimulation.
Animals↗