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Biomedical subjects

M F Piercey

Publications and source records attributed to M F Piercey.

At least 73 records · Page 4Linked to original sources
PubMed1987

Electrophysiological evaluation of a partial agonist of dopamine receptors.

The ergot derivative trans-dihydrolisuride (TDHL) was tested for its effects on firing rates of dopaminergic (DA) neurons located in the substantia nigra pars compacta of chloral hydrate-anesthetized rats. Using extracellular single-barreled microelectrodes, DA neurons were identified by their long duration, positive-negative action potentials and their slow bursting pattern of spontaneous firing, as well as by the location of recording sites through histological recoveries of dye deposits. Like haloperidol and clozapine, which are full DA receptor antagonists, TDHL antagonized the depression in DA neuron firing induced by systemic amphetamine. However, where full antagonists completely reversed the amphetamine effect, TDHL could do so only partially, the maximal effect being around half. Like DA agonists, but unlike DA antagonists, TDHL also depressed the spontaneous firing rates of DA neurons. But whereas the full agonist apomorphine completely inhibited firing of DA neurons, TDHL only depressed firing rates by about half, even at high doses. These data support the contention that TDHL is a partial DA agonist.

Amphetamine↗
PubMed1986

Analgesic activities of spinal cord substance P antagonists implicate substance P as a neurotransmitter of pain sensation.

Substance P (SP) injected into intraspinal (i.s.) spaces caused mice to vigorously scratch and bite their skins in an apparent reaction to a perceived cutaneous sensation. The scratching behavior was similar to the reciprocal hindlimb-scratching syndrome (RHS) described for intracranial (i.c.) SP injections. Radiotracer experiments, as well as potency and latency measurements, demonstrated that SP-induced scratching, whether induced by the i.c. or i.s. route, was due to SP receptor stimulation in the cervicothoracic cord. Similarly, biting was due to SP stimulation of the lumbosacral spinal cord. Mice coated with capsaicin, an irritant chemical, scratched and bit the coated areas in a manner similar to animals injected with i.s. SP. Standard analgesics depressed this scratching behavior elicited by topical capsaicin. Non-analgesic drugs, with the exception of amphetamine, did not affect capsaicin-induced pain. It is concluded that i.s. SP induces a painful sensory experience. Some piperazinone derivatives of substance P's C-terminal hexapeptide are shown to specifically antagonize the scratching induced by i.s. SP with little or no effect on motor behavior. These antagonists depressed scratching elicited by topical capsaicin and were analgesic on the hot-plate test. It is concluded that SP is a natural neurotransmitter for pain and that antagonism of endogenous SP systems causes analgesia.

Analgesics↗
PubMed1985

The supersensitivity of dopaminergic neurons to apomorphine in rats following chronic haloperidol.

Supersensitivity to apomorphine's inhibitory effect on dopamine neurons was induced in Sprague-Dawley rats by chronically administering haloperidol. It is concluded that the increased sensitivity of dopamine neurons to apomorphine may be linked to its influence on autoreceptors. The possibility that autoreceptor supersensitivity could contribute to enhancement of antipsychotic therapy is discussed.

Animals↗
PubMed1985

Stereospecificity of SP1 and SP2 substance P receptors.

Previous studies with N-terminal fragments of substance P (SP) have suggested the existence of two separate SP receptor populations. SP1 receptors are found in guinea pig ilea and rat colons. SP2 receptors are found in mouse spinal cords and rat salivary glands. We have now found that substitution of Gly9 in substance P's C-terminal hexapeptide leads to an analog (L-Pro9 SP6-11) which selectively and potently stimulates SP2 receptors. In contrast, substitution of the same residue with D-Proline results in a potent and selective agonist for SP1 receptors. The data dramatically confirm the distinction between SP1 and SP2 receptors and demonstrate that the two receptors have distinct stereochemical architectures.

Animals↗
PubMed1982

Use of substance P fragments to differentiate substance P receptors of different tissues.

The C- and N-terminal fragments of substance P were compared to the parent molecule with respect to their ability to: (a) contract the isolated guinea pig ileum, (b) induce salivation in the rat, (c) excite single cat dorsal horn neurones, and (d) induce scratching by intracranial injections in mice. C-terminal fragments as small as the heptapeptide were potent SP agonists on all assay systems. C-terminal fragments containing five amino acids or less were, at most, only weakly active. The C-terminal hexapeptide was a potent SP receptor stimulant on the isolated guinea pig ileum and, when directly applied by microiontophoresis, on cat dorsal horn neurons. However, the same compound was only 2-5% as potent as substance P in eliciting salivation and scratching in vivo, an indication that this fragment may be especially labile to enzymatic degradation. N-terminal fragments were totally inactive on the isolated guinea pig ileum. On the rat salivation and central nervous system assays, however, N-terminal fragments were capable of weak SP-like activity. It is concluded that SP receptors exist in multiple forms which we have labelled SP1 and SP2 receptors for those insensitive or sensitive to N-terminal fragments, respectively.

Animals↗
PubMed1981

Sensory and motor functions of spinal cord substance P.

Low doses of D-Pro2-D-Phe7-D-Trp9-substance P, as specific substance P antagonist, depressed the scratching and biting behaviors elicited by intrathecal injections of substance P, and cutaneous application of algesic substances. Higher antagonist doses caused hindlimb paralysis. This suggests that substance P is a neurotransmitter for primary nociceptor afferents and may also have an important function in motor control.

Animals↗
PubMed1981

Spinal and Supraspinal sites for morphine and nefopam analgesia in the mouse.

Using the tail-flick and hot-plate assays, morphine and nefopam were tested for analgesic activity following intraperitoneal (i.p.), intracranial (i.c.) and intraspinal (i.s.) injection in mice. By the i.p. route, morphine was equipotent on both analgesic tests. Nefopam was one-third as potent as morphine on the hot-plate test, but did not affect the tail-flick. Intracranial morphine was more effective on the hot-plate than on the tail-flick, but i.s. morphine was most potent on the tail-flick. Naloxone, 0.5 mg/kg i.p., totally reversed morphine's effects on the tail-flick, but only partially reversed these actions on the hot-plate, suggesting the possibility that morphine's effects on the mouse hot-plate test may be mediated via multiple receptor types. Nefopam was more potent by the i.c. route than by the i.p. route, but its was inactive spinally. Nefopam analgesia was unaffected by naloxone treatment. It is concluded that nefopam is a novel, centrally acting, non-narcotic analgesic.

Analgesia↗
PubMed1980

Morphine does not antagonize the substance P mediated excitation of dorsal horn neurons.

Multibarrelled microelectrodes were used to test the effects of iontophoretically released substance P (SP), morphine, glutamate, and naloxone on spinal cord dorsal horn neurons. Cells excited by SP were also excited by noxious stimuli, a finding consistent with the hypothesis that SP is the neurotransmitter released by primary nociceptor afferents to excite dorsal horn neurons. Iontophoretic morphine failed to depress the SP-induced discharges. Indeed, iontophoretic morphine frequently potentiated the SP responses. In addition to potentiating SP-induced discharges, iontophoretic morphine frequently increased both the spontaneous activity of dorsal horn neurons and the activity evoked in these cells by noxious cutaneous heat and iontophoretic glutamate. Naloxone did not antagonize these excitatory effects. Intravenous morphine only depressed spontaneous discharges. Nevertheless, iontophoretic morphine still produced excitatory effects in spinal animals pretreated with analgesic doses of intravenous morphine. It is concluded that such excitatory effects are toxic actions indicative of supratherapeutic morphine concentrations in the vicinity of the neuron being studied. Intravenously administered morphine depressed the spontaneous activity of dorsal horn neurons of spinal cats, but failed to depress their responses to SP. Morphine also failed to antagonize SP's biological effects in peripheral systems (contraction of isolated guinea pig ileum, rabbit hypotensive effect, rat sialogogic response). It is concluded that morphine is not a substance P receptor antagonist. The results are discussed with respect to the hypotheses that (1) the spinal analgesic effects of systemically administered morphine occur on presynaptic terminals of sensory neurons, and (2) an SP antagonist might be a unique analgesic agent.

Animals↗
PubMed1980

Morphine depresses dorsal horn neuron responses to controlled noxious and non-noxious cutaneous stimulation.

Dorsal horn neurons of unanesthetized, decerebrated, low spinal cats were excited by controlled noxious and non-noxious natural stimulation as well as by intense transcutaneous electrical stimulation. Intravenous morphine (0.3--3.0 mg/kg) depressed the spontaneous activity, the electrically evoked discharge and the response to noxious cutaneous heat (greater than 45 degree C) of nociceptive dorsal horn neurons. In those nociceptive neurons receiving convergent non-noxious inputs, morphine also depressed responses to non-noxious cutaneous air-puff stimulation. The above morphine effects were all reserved by 0.3 mg/kg of naloxone i.v. In neurons, which were purely non-nociceptive, morphine had little or no effect on either spontaneous activity or evoked responses to non-noxious stimuli. These findings suggest that: 1) morphine has a spinal site of action in which noxious as well as non-noxious inputs are decreased; and 2) there is a group of purely non-nociceptive dorsal horn neurons which are not influenced by the spinal actions of morphine.

Action Potentials↗
PubMed1980

A quantitative analgesic assay in the rabbit based on the response to tooth pulp stimulation.

A DC ramp voltage was used to stimulate rabbit tooth pulps. Thresholds to elicit chewing movements were extremely stable in the absence of drug treatment. Using cumulative dosing of analgesic drugs, potency and efficacy measurements could be readily obtained. Narcotic analgesics were the most effective analgesics on this test, followed by two centrally acting non-narcotics (nefopam and baclofen). Antipyretic/anti-inflammatory analgesics and centrally acting non-analgesic drugs elevated thresholds by lesser amounts or were inactive. It is concluded that the rabbit tooth pulp assay is suitable for the qualitative and quantitative determination of analgesic activity.

Analgesics↗
PubMed1979

Effects of intravenous baclofen on dorsal horn neurons of spinal cats.

Intravenous baclofen (1 mg/kg) abolished or severely attenuated the high threshold late component (but not the low threshold early component of long duration (greater than 150 msec) discharges evoked in cat dorsal horn neurons by intense transcutaneous electrical stimulation. Baclofen similarly reduced the spontaneous activities and discharges evoked by intra-arterial bradykinin in these same cells. These powerful inhibitions of dorsal horn interneurons may be the basis of baclofen's reported analgesic actions and could contribute to depression in reflex excitability of motoneurons.

Aminobutyrates↗
PubMed1979

Naloxone inhibits the anti-diarrhoeal activity of loperamide.

1 Subcutaneous prostaglandin E2 (2.5 mg/kg) produces profuse diarrhoea in fed rats. 2 Pretreatment of rats with subcutaneous loperamide (1.0 mg/kg) completely prevents prostaglandin-induced diarrhoea. If naloxone is administered prior to loperamide injections the activity of the antidiarrhoeal compound is completely destroyed. 3 These data provide strong evidence that the antidiarrhoeal activity of loperamide is mediated via the opiate receptor.

Animals↗
PubMed1976

Respiratory rhythmicity in the cat.

Brain stem respiratory neuron activity in the cat was studied in relation to efferent outflow (phrenic discharge) under the influence of several forcing inputs: 1) CO2 tension: hypocapnia produces disappearance of firing in some neurons, and conversion of respiratory-modulated to continuous (tonic) firing in others. 2) Lung inflation: during the Bruer-Hering reflex, some neurons have "classical" responses and others have "paradoxical" responses (i.e., opposite in direction to peripheral discharge). 3) Electrical stimulation: stimulus trains to the pneumotaxic center region (rostral lateral pons) produce phase-switching, whose threshold is: a) sharp (indicating action of positive-feedback mechanisms), and b) dependent on timing of stimulus delivery (indicating continuous excitability changes during each respiratory phase). Auto- and crosscorrelation analysis revealed the existence of short-term interactions between: a) medullary inspiratory (I) neurons and phrenic motoneurons; b) pairs of medullary I neurons; c) medullary I neurons and expiratory (E) neurons. A model of the respiratory oscillator is presented, in which the processes of conversion of tonic to phasic activity and switching of the respiratory phases are explained by recurrent excitatory and inhibitory loops.

Action Potentials↗