Biomedical subjects
H J Haigler
Publications and source records attributed to H J Haigler.
The National Institute of Mental Health-Psychotherapeutic Medications Development Program (PMDP): status 1993.
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Psychotherapeutic Medications Development Program (PMDP).
The Psychotherapeutic Medications Development Program (PMDP) of the National Institute of Mental Health was established in 1990. The purpose of the PMDP is to improve, enhance, and speed the development of new medications and improve the therapeutic usefulness of existing medications for the treatment of mental illness. The PMDP will fulfill this mission by implementing four initiatives. In the drug discovery and development initiative, the PMDP will aid in the development of promising new drugs. This initiative will also include improving the therapeutic usefulness of existing medications. In the technology transfer initiative, PMDP will improve the technology transfer from academic and government researchers to the pharmaceutical industry; improve the dissemination of information concerning technology transfer opportunities as it pertains to psychotherapeutic medications; and enhance technology transfer by acting as a broker to bring interested parties together. For the third initiative, the PMDP will develop and maintain a capability to clinically evaluate psychotherapeutic medications. The PMDP will also act to facilitate the development and testing of new concepts and models of mental illness. There is a detailed description of the steps that are involved in developing a new chemical entity (NCE) from the conceptual stage to a medication that is approved for the treatment of a particular illness. The pharmaceutical industry estimates that this medication development process costs $238 million.
National Institute of Mental Health: Psychotherapeutic Medications Development Program.
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Biochemical assay of Alzheimer's disease--associated protein(s) in human brain tissue. A clinical study.
The concentration of Alzheimer's disease-associated protein (ADAP) was measured in postmortem brain tissue samples of temporal or frontal cortex from 111 human brains using a sandwich immunoassay. Alzheimer's disease-associated protein has three major ALZ-50-reactive subunits, including A-68. This assay utilizes ALZ-50 and a rabbit antibody raised against a highly ADAP-enriched brain protein fraction. The frequently observed cross-reactivity of ALZ-50 with normal brain components in direct immunoassays is minimized by this configuration. There were 27 normal controls, 28 neurologic disease controls, and 56 Alzheimer's disease cases. The normal control and neurologic disease control cases had essentially no detectable level of ADAP, while ADAP was clearly detected in 85.7% of the Alzheimer's disease cases. Clinical dementia, neuritic plaques, and old age per se are not correlated with increased ADAP levels. This biochemical assay of ADAP may prove to be helpful as an adjunct in the clinicopathologic diagnosis of Alzheimer's disease.
The human endonexin II (ENX2) gene is located at 4q28----q32.
A relatively recently identified family of structurally similar Ca2(+)-dependent phospholipid binding proteins is called the annexin gene family. At least seven genes are known, although their exact functions are unclear. The endonexin II gene (ENX2), one member of the gene family, is assigned to 4q28----q32 using both Southern transfer analysis of human x rodent somatic cell hybrid DNAs and in situ chromosome hybridization. One of the lipocortin II genes, another annexin, had previously been assigned to the long arm of chromosome 4.
Met-enkephalin, age and anatomy: a microiontophoretic study in the hippocampus.
Met-enkephalin, administered microiontophoretically, produced a greater increase in firing in cells in area CA 3-4 in the hippocampus of both young and aged Fisher 344 rats than it did in the CA 1 area. Furthermore, the effect of met-enkephalin on neuronal firing rates was not as great in old rats as it was in young rats. Finally, 20-40 nA of met-enkephalin produced an increase in firing in old rats that was equivalent to the difference (2.5 spikes/sec) in baseline firing between old (2.6 spikes/sec) and young rats (5.1 spikes/sec).
Neurophysiological effects of opiates in the CNS.
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Acetylcholine, aging and anatomy: differential effects in the hippocampus.
The response to acetylcholine (ACh) administered microiontophoretically was determined for single units in CA1 and CA3-4 areas of the hippocampi of both young (3-5 months) and old (24-26 months) Fisher 344 rats. Single units in CA1 showed a greater response to ACh (20 nA) than single units in CA3-4 in young and in old rats. However, the response to ACh in single units of young rats was significantly greater than in single units of old rats. Baseline firing rates in old rats were lower than those in young rats. However, there was no difference in baseline firing rates between the two areas of the hippocampus indicating that the differential response to ACh as a function of area cannot be attributed to a difference in baseline firing rate.
Prefrontal influences upon the midbrain: a possible route for pain modulation.
After implanting stimulating electrodes in the prefrontal cortex (PFC) of adult male rats, the response to PFC stimulation was studied in widely scattered neurons of the midbrain. Subsequent testing was performed to determine if the firing rates of PFC-responsive neurons could also be altered by either a noxious stimulus (foot pinch) or the microiontophoretic administration of various neurotransmitter substances (methionine-enkephalin, ME; norepinephrine, NE; acetylcholine, ACh). Numerous mesencephalic neurons were identified which altered their spontaneous firing rates in response to PFC stimulation. Following PFC stimulation, most (71%) neurons decreased their firing rates. It was also noted that most (78%) PFC-responsive neurons were also responsive to noxious stimulation. Of these neurons, 65% altered their firing rates in a similar manner in response to both PFC and noxious stimuli. The remainder of the neurons which altered their firing rates in response to both PFC and noxious stimulation responded to the two types of stimuli in opposite manners. Of this latter type, it was found that when PFC and noxious stimuli were administered concurrently, PFC stimulation abolished the response to the noxious stimulus. It was also observed that the microiontophoretic administration of either ME or NE frequently (100% and 52% respectively) mimicked the response to PFC stimulation, thereby suggesting that these neurotransmitters may be involved in mediating the PFC influence upon neurons in the midbrain.
Effects of clonidine on neuronal firing evoked by a noxious stimulus.
When norepinephrine was applied microiontophoretically to certain neurons in the pontine reticular formation of rats, it produced an increase in neuronal firing like that produced by noxious stimulation. Previous studies have shown that both noxious stimulus- and norepinephrine-evoked increases in neuronal firing are mediated by alpha-adrenoceptors. These neurons were unresponsive to non-noxious stimuli, suggesting that they might play a role in nociception. Microiontophoretic or systemic administration of the selective alpha 2-adrenoceptor agonist clonidine significantly attenuated noxious stimulus-evoked firing, but had little effect on firing evoked by norepinephrine. This effect of clonidine could be prevented by the alpha 2-adrenoceptor antagonists piperoxan and yohimbine. These antagonists, when given alone, increased noxious stimulus-evoked firing, but had no effect on firing evoked by norepinephrine. In contrast, the selective alpha 1-adrenoceptor antagonist ARC-239 (2-(2,4-(o-methoxyphenyl)-piperazin-1-yl)ethyl-4,4-dimethyl-1,3-(2 H,4) isoquinolindione dihydrochloride) attenuated both noxious stimulus- and norepinephrine-evoked firing. These data are consistent with the hypothesis that presynaptic alpha 2-adrenoceptors modulate the release of norepinephrine. Furthermore, these data suggest that the pontine reticular formation is one site at which clonidine could act to produce analgesia.
Paralemniscal reticular formation: response of cells to a noxious stimulus.
Extracellular single unit recordings were made in the paralemniscal reticular formation in adult male rats. A majority of the cells studied were characterized as nociceptive because a noxious stimulus evoked a change (either an increase or decrease) in their spontaneous firing rates. Norepinephrine (NE) administered microiontophoretically usually mimicked the response to the noxious stimulus (foot pinch). After a neuron had been characterized with respect to its response to NE and the noxious stimulus, horseradish peroxidase (HRP) was iontophoretically ejected from the micropipette. Following iontophoresis of HRP into the paralemniscal reticular formation, retrograde and orthograde labeling was observed in the periaqueductal gray and the nucleus raphe magnus. These data support a possible role of the paralemniscal reticular formation in an endogenous analgesic system.
Interactions of morphine with putative neurotransmitters in the mesencephalic reticular formation.
Acetylcholine (ACh) and norepinephrine (NE) have been identified previously as putative nociceptive neurotransmitters in the mesencephalic reticular formation (MRF) of the rat because they frequently mimic the change in neuronal firing (usually an increase) evoked by a noxious stimulus (NS). The purpose of this study was to determine if 1.) morphine (M) acts to prevent the increase in firing evoked by a NS by blocking the effects of either of these two neurotransmitters and 2.) if this effect is a specific narcotic effect. Using the technique of microiontophoresis in conjunction with extracellular recording, we located single units in the MRF in which 1.) neuronal firing was accelerated by a NS: 2.) M blocked this response; and 3.) either ACh or NE mimicked the effect of the NS. Neurons meeting these three criteria were studied further to determine if morphine would also block the response to either of the neurotransmitters and if this was a specific narcotic effect. We found that morphine blocked the increase in neuronal firing evoked by the NS and ACh or the NS and NE in over 50% of the cells meeting the above criteria. Some neurons were found in which both ACh and NE mimicked the NS and M blocked all three responses. This blockade of these neurotransmitters was a specific narcotic effect because it could be reversed by the systemic administration of naloxone. These data lead to the tentative hypothesis that M, acting via an opiate receptor, blocks the increase in neuronal firing evoked by a NS by blocking the postsynaptic effects of either ACh or NE. This may be one of the mechanisms by which morphine acts to produce analgesia.
Effects of serotonin and morphine on spontaneous and evoked firing of nociceptive neurons in the trigeminal spinal nucleus of rats.
Spontaneously firing neurons that were responsive to noxious face pinch or noxious heat were studied in the trigeminal spinal nucleus of the rat brain. These neurons responded with either an increase or decrease in firing rate. In these neurons serotonin (5-hydroxytryptamine; 5-HT) apparently acts through two mechanisms to attenuate the response to a noxious stimulus. One mechanism is mimicked by morphine; these two drugs block the response to the noxious stimuli without having a consistent effect on spontaneous firing. The effects of the two drugs were somewhat selective depending on the noxious stimulus used and the effect of the noxious stimulus; morphine and 5-HT were more effective in blocking the increase in firing rate evoked by the face pinch but 5-HT and morphine were more effective in blocking the decrease in firing rate evoked by the noxious heat stimulus. Interestingly, the direction of the response to a particular noxious stimulus frequently predicted whether or not both morphine and 5-HT would act on the same or different neurons. A second mechanism by which 5-HT, but not morphine, acted was to change the spontaneous firing in a direction opposite that evoked by the noxious stimulus. This type of effect apparently modulated the response to a noxious stimulus by changing the spontaneous firing rate such that a noxious stimulus had to be more intense before it could significantly alter the neuronal firing in the opposite direction. Morphine occasionally produced a change in firing pattern in neurons; this effect remains to be documented more extensively.
Comparison of the analgesic effects of dimethyl sulfoxide and morphine.
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Characteristics of adrenoceptors in a nociceptive pathway in the mesencephalic reticular formation of the rat.
Norepinephrine (NE) may be a neurotransmitter in a nociceptive pathway in the mesencephalic reticular formation (MRF) of the rat. When NE is applied microiontophoretically to certain neurons in rat MRF, it produces a change in neuronal firing rate similar to that produced by a noxious stimulus (foot pinch) in these neurons. If NE is a neurotransmitter involved in the transmission of nociceptive information in the MRF, specific adrenergic receptor antagonists, administered microiontophoretically, should block both the firing evoked by NE, administered microiontophoretically, and the firing evoked by foot pinch in these neurons. When phentolamine (an alpha adrenoceptor antagonist) was administered microiontophoretically it blocked the increases in neuronal firing rate evoked either by foot pinch or by NE. In contrast, propranolol (a beta adrenoceptor antagonist) rarely blocked the firing evoked by either foot pinch or by the microiontophoretic administration of NE. Thus, it appears that if NE is involved in the transmission of nociceptive information in the MRF of the rat, this information transfer is mediated by alpha adrenergic receptors.
Characteristics of extravascular serotonin receptors in the brain.
At least three types of extravascular 5-HT receptors are present in the brain. Peripheral 5-HT antagonists mimic the inhibitory effects but block the excitatory effects 5-HT in the brain. Although the forebrain serotonergic system is apparently not involved in nociception, the MPR may be an important link in an antinociceptive system; this system may be activated by morphine. A decrease in the amount of 5-HT released by projections from the MPR to the trigeminal nucleus could be partially responsible for the pain experienced in migraine headache. Drugs useful in treating migraine headache may mimic 5-HT at synapses in the trigeminal nucleus that are associated with projections from the MPR. This possibility remains to be tested experimentally.
DMSO (dimethyl sulfoxide), morphine and analgesia.
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