PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Strychnine”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1992

Comparison of binding at strychnine-sensitive (inhibitory glycine receptor) and strychnine-insensitive (N-methyl-D-aspartate receptor) glycine binding sites.

We compared, for a number of ligands to the two receptors, the displacement of [3H]strychnine binding to the glycine-gated chloride channel of spinal cord and brainstem synaptic membranes to the displacement of [3H]glycine binding to the NMDA receptor complex of hippocampal and cortex synaptic membranes. Glycine and beta-alanine are recognized by both receptors. In the NMDA receptor glycine antagonists, the kynurenic acids, most of the quinoxalinediones, and the (R)-enantiomer of HA-966 had little affinity at the strychnine-sensitive site. Surprisingly, the quinoxalinedione widely used as an AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor antagonist, NBQX (2,3-dihydro-6-nitro-sulfamoylbenzo[f]quinoxaline-2,3-dione) displaced [3H]strychnine binding (IC50 = 11 microM) and to a lesser extent [3H]glycine binding (IC50 = 119 microM). Of the compounds tested, only strychnine, brucine, taurine and (S)-HA-966 were more potent displacers of [3H]strychnine than of glycine binding. Generally, the two glycine recognition sites appear to have remarkably different structural requirements.

Animals↗
PubMed1977

The binding of strychnine and strychnine analogs to synaptic membranes of rat brainstem and spinal cord.

Crude synaptic membranes were isolated from rat pons, medulla and spinal cord by differential centrifugation. The specific binding of [3H]strychnine, obtained by subtracting from the bound radioactivity the amount not displaced by 50 micronm unlabeled strychnine, was saturable with a KD value of 12 nM. The dissociation constants (KD values) for the binding of several strychnine analogs to the strychnine site in vitro were determined and found to be highly correlated with the convulsant and lethal effects in the mouse. However, neither the biological activities in the mouse nor the binding activity in vitro correlated with the n-octanol-water distribution coefficients. The results are in accord with the concept that the [3H]strychnine binding site detected in vitro is the site of pharmacological activity in vivo.

Animals↗
PubMed1997

Strychnine-sensitive and strychnine-insensitive glycine binding sites in the spinal cord of the wobbler mouse.

Using quantitative autoradiography, the strychnine-sensitive glycine site and strychnine-insensitive glycine site of the N-methyl-D-aspartate receptor were analyzed in the cervical segment of the spinal cord of the wobbler mouse, which is a purported model of human motor neuron diseases. Significantly increased density of the strychnine-sensitive site was found in the lamina II-inner (+17%) and laminae III & IV (+17%) of wobbler mice. The strychnine-insensitive site was also increased in lamina I & II-outer (+15%), lamina II-inner (+15%), laminae III & IV (+48%), laminae V-VIII (+43%) and lamina X (+26%) of wobbler mice. However, no significant differences were observed for the both sites in the ventral horn where motor neurons are located. These findings suggest that both inhibitory and excitatory-associated glycinergic dysfunctions are involved in the wobbler mouse motor neuron disease.

Animals↗
PubMed1996

Interactions of glycine and strychnine with their receptor recognition sites in mouse spinal cord.

Interactions between the inhibitory neurotransmitter glycine and its receptor antagonist strychnine have been studied in mouse spinal cord membranes and both agents employed to protect against residue selective protein modifying reagents in order to identify contact residues for ligand binding. Glycine was found to behave as a full competitive inhibitor of [3H]-strychnine binding, provided that precautions were taken to prevent radioligand binding to the glass-fibre filters used to terminate the assays. Hill coefficients for the glycine inhibition of [3H]-strychnine binding were not significantly different from one, indicating a lack of cooperative interactions. For the protection experiments, N-bromosuccinimide, tetranitromethane, diethylpyrocarbonate and 2,3-butanedione were used under conditions selective for tryptophan, tyrosine, histidine and arginine residues, respectively. Of these reagents, N-bromosuccinimide, tetranitromethane and diethylpyrocarbonate caused a decrease in total [3H]-strychnine binding without affecting the ability of unlabelled strychnine to compete. In contrast, the same reagents disrupted the ability of glycine to inhibit [3H]-strychnine binding. The presence of either excess glycine (10(-2) M) or strychnine (10(-4) M) during the above treatments was found to prevent the decrease in total and strychnine-specific [3H]-strychnine binding. However, only in the case of diethylpyrocarbonate treatment were both agonist and antagonist able to protect against the loss of glycine-specific [3H]-strychnine binding. The reagent 2,3-butanedione caused an increase in total and strychnine-specific [3H]-strychnine binding (which we have shown elsewhere to be at a site unrelated to the inhibitory glycine receptor). When the above protein modifying reagents were applied under the same conditions to specific strychnine binding antibodies, all four caused significant decreases in subsequent [3H]-strychnine binding. Strychnine was found to afford significant protection of the antibodies against N-bromosuccinimide, tetranitromethane and 2,3-butanedione, but not against diethylpyrocarbonate. Our results suggest that glycine and strychnine compete at overlapping but conformationally distinct sites on the receptor. Tyrosine, tryptophan, histidine and arginine residues are implicated as strychnine contact residues with a shared role for histidine in the recognition of glycine.

Animals↗
PubMed1994

Strychnine-induced seizures in mice: the role of noradrenaline.

1. The effects of some noradrenergic agents on seizures induced by strychnine were investigated in mice. 2. Strychnine (0.5-4 mg/kg, i.p.) dose-dependently produced tonic seizures. 3. DOPS (4-8 mg/kg, i.p.) significantly shortened the latency of seizures elicited by strychnine (2 mg/kg, i.p.). Similarly, DOPS (4 mg/kg, i.p.) effectively increased the incidence and significantly shortened the latency of seizures induced by strychnine (1 mg/kg, i.p.). 4. Imipramine (20-40 mg/kg, i.p.) and pargyline (200 mg/kg, i.p.) significantly shortened the latency of strychnine (2 mg/kg, i.p.)-induced seizures. 5. Phentolamine (5-20 mg/kg, i.p.) effectively antagonised the seizures elicited by strychnine (2 mg/kg, i.p.). Furthermore, phentolamine (10 mg/kg, i.p.) attenuated the seizure-potentiating effect of DOPS (4 mg/kg, i.p.). 6. Propranolol (0.5-2 mg/kg, i.p.) and prazosin (1-2 mg/kg, i.p.) reduced the incidence and significantly delayed the latency of seizures induced by strychnine (2 mg/kg, i.p.). 7. Reserpine (5-10 mg/kg, i.p.) significantly prolonged the latency of strychnine (2 mg/kg, i.p.)-induced seizures. 8. Clonidine (0.25-1 mg/kg, i.p.) dose-dependently and significantly antagonised strychnine (2 mg/kg, i.p.)-induced seizures. 9. Idazoxan (1-4 mg/kg, i.p.) in a dose related manner significantly shortened the latency of seizures induced by strychnine (2 mg/kg, i.p.). Similarly, idazoxan (2 mg/kg, i.p.) profoundly potentiated seizures elicited by strychnine (1 mg/kg, i.p.). Idazoxan (4 mg/kg, i.p.) significantly antagonised the protective effect of clonidine (1 mg/kg, i.p.) against strychnine (2 mg/kg, i.p.)-induced seizures. 10. Disulfiram (3 x 25 - 3 x 100 mg/kg, i.p.) significantly attenuated strychnine (2 mg/kg, i.p.)-induced seizures. DOPS (4 mg/kg, i.p.) significantly potentiated strychnine seizures in disulfiram (3 x 100 mg/kg, i.p.)-pretreated animals. 11. These results indicate that enhancement of noradrenergic neurotransmission potentiates strychnine seizures in mice.

Adrenergic alpha-Antagonists↗
PubMed1994

Strychnine and glycine protect renal proximal tubules from various nephrotoxicants and act in the late phase of necrotic cell injury.

We have previously shown that strychnine mimics the cytoprotective properties of glycine in renal proximal tubule (RPT) suspensions exposed to antimycin A (AA). The aims of this study were to determine whether the cytoprotective properties of strychnine applied to various types of nephrotoxicants and to examine the temporal aspects of the cytoprotection of glycine and strychnine. Tubular release of LDH activity was used as a marker of cell death. Glycine (2 mM) or strychnine (1 mM) added 5 min prior to the toxicant decreased LDH release in rabbit RPT suspensions exposed to 25 microM tetrafluoroethyl-L-cysteine (TFEC), 10 microM HgCl2, 0.5 mM t-butyl hydroperoxide (TBHP), or 0.2 mM bromohydroquinone (BHQ) for 4 hr, or 2 mM sodium cyanide (NaCN) for 2 hr. The relative rank order of effectiveness of glycine and strychnine was NaCN = TFEC > BHQ > DCVC >> TBHP > HgCl2. The temporal aspects of strychnine and glycine protection were examined by exposing RPT to either AA or TFEC for 1 or 3 hr, respectively, and then adding either 1 mM glycine or 1 mM strychnine. Glycine and strychnine decreased LDH release in AA-treated RPT at 1.25 and 2 hr and TFEC-treated RPT at 4 hr. In addition, when RPT exposed to AA or TFEC and treated with strychnine or glycine were washed at either 1 or 4 hr, protection was eliminated at later time points. When glycine was added to RPT treated with either PCBC, TFEC, or DCVC 5 min prior to or 30, 60, 120, and 180 min following toxicant addition, LDH release was reduced at all time points. These results demonstrate that strychnine and glycine protect RPT from a variety of diverse nephrotoxicants, strychnine and glycine do not need to be present at the time of toxic insult, strychnine and glycine cytoprotection is reversible, and strychnine and glycine act in the late phase of necrotic cell injury.

Animals↗
PubMed1984

Influence of levodopa, apomorphine and 3,4-dihydroxyphenylserine (DOPS) on strychnine-induced seizures in mice.

The effects of levodopa, apomorphine and 3,4-dihydroxyphenylserine (DOPS) on tonic seizures elicited by strychnine were investigated in mice. Levodopa (6.25-100 mg/kg), apomorphine (0.2-0.8 mg/kg) and FLA-63 (12.5 mg/kg) profoundly delayed the onset and reduced the incidence of strychnine seizures. In addition, these drugs decreased strychnine-induced mortality. DOPS (1-16 mg/kg) apparently shortened the onset of strychnine seizures and altered strychnine-induced mortality in a dose-dependent manner; low doses (1-2 mg/kg) enhanced while moderate doses (4-8 mg/kg) reduced the mortality rate. FLA-63 (12.5 mg/kg) potentiated the anticonvulsant effect of low doses of levodopa (6.25-12.5 mg/kg) while it had no significant influence on the anticonvulsant effect of higher doses (25-100 mg/kg) of levodopa. In addition, the onset of strychnine seizure was further delayed by FLA-63. Haloperidol (0.5 mg/kg) potentiated the convulsant effect of strychnine (1 mg/kg) as well as strychnine-induced mortality. It also antagonised the protective effect of levodopa (12.5 and 100 mg/kg) against strychnine (1 mg/kg). Phentolamine (5 mg/kg) and +/- propranolol (1 mg/kg) antagonised strychnine seizures. Strychnine-induced mortality was also reduced by these drugs. In addition, the effects of DOPS (2 mg/kg) on strychnine seizures were antagonised by phentolamine and propranolol. These results indicate that enhancement of dopaminergic and noradrenergic neurotransmission respectively attenuate and potentiate strychnine seizures in mice.

Animals↗
PubMed1997

Comparable dose-dependent inhibition of AP-7 sensitive strychnine-induced allodynia and paw pinch-induced nociception by mexiletine in the rat.

The blockade of spinal glycine receptors with intrathecal (i.t.) strychnine produces segmentally-localized allodynia in the rat; a reversible and highly reproducible effect that is attained without peripheral or central nerve injury. We investigated the effect of i.v. mexiletine, an orally active congener of lidocaine, on strychnine allodynia and compared the dose-response relationship of mexiletine in normal (noxious paw pinch) versus abnormal (i.t. strychnine) nociceptive conditions. In addition, we determined the dose-response effect of i.t. AP-7 (an NMDA antagonist) on strychnine allodynia. Male, Sprague-Dawley rats, fitted with chronic i.t. catheters, were lightly anesthetized with urethane. Stimulus evoked changes in blood pressure and heart rate were recorded from the left carotid artery and cortical electroence-phalographic (EEG) activity was continuously monitored using subdermal needle electrodes. After i.t. strychnine (40 micrograms), repetitive brushing of the hair (hair deflection) evoked a progressive increase in mean arterial pressure and heart rate, an abrupt motor withdrawal response, and desynchronization of the EEG, equivalent to those elicited by the chemical nociceptive agent, mustard oil (without strychnine). Pretreatment with mexiletine (5-30 mg/kg i.v. 5 min before i.t. strychnine) dose-dependently inhibited the responses evoked by noxious hind paw pinch (no strychnine) and hair deflection (after i.t. strychnine) with equal potency (ED50's = 9.1-17 mg/kg). Below 30 mg/kg, this effect was achieved without a change in EEG synchrony (cortical activity reflecting the level of anesthesia) and without affecting motor efferent pathways. Strychnine allodynia was also significantly blocked by i.t. AP-7. The ED50's and 95% confidence intervals were 1.1 micrograms (0.7-1.8) for mean arterial pressure, 1.7 micrograms (0.5-6.0) for heart rate, and 0.4 microgram (0.07-2.0) for withdrawal duration. Cortical EEG synchrony was unchanged after i.t. AP-7 consistent with a spinal site of action. The data indicate that: (i) robust allodynia can be selectively induced with i.t. strychnine in animals whose somatosensory systems are otherwise normal; (ii) sub-anesthetic doses of i.v. mexiletine inhibit the abnormal responses to low-threshold (A-fiber) afferent input in the strychnine model of allodynia (i.e., in the absence of peripheral or central nerve injury) at doses which affect normal nociception; and (iii) in the presence of i.t. strychnine, low-threshold afferent input activates a spinal NMDA-receptor mediated process normally restricted to noxious afferent input. Systemic mexiletine may have an important spinal site of action in abnormal pain states.

2-Amino-5-phosphonovalerate↗
PubMed1997

Altered receptive fields and sensory modalities of rat VPL thalamic neurons during spinal strychnine-induced allodynia.

Altered receptive fields and sensory modalities of rat VPL thalamic neurons during spinal strychnine-induced allodynia. J. Neurophysiol. 78: 2296-2308, 1997. Allodynia is an unpleasant sequela of neural injury or neuropathy that is characterized by the inappropriate perception of light tactile stimuli as pain. This condition may be modeled experimentally in animals by the intrathecal (i.t.) administration of strychnine, a glycine receptor antagonist. Thus after i.t. strychnine, otherwise innocuous tactile stimuli evoke behavioral and autonomic responses that normally are elicited only by noxious stimuli. The current study was undertaken to determine how i.t. strychnine alters the spinal processing of somatosensory input by examining the responses of neurons in the ventroposterolateral thalamic nucleus. Extracellular, single-unit recordings were conducted in the lateral thalamus of 19 urethan-anaesthetized, male, Wistar rats (342 +/- 44 g; mean +/- SD). Receptive fields and responses to noxious and innocuous cutaneous stimuli were determined for 19 units (1 per animal) before and immediately after i.t. strychnine (40 microgram). Eighteen of the animals developed allodynia as evidenced by the ability of otherwise innocuous brush or air jet stimuli to evoke cardiovascular and/or motor reflexes. All (3) of the nociceptive-specific units became responsive to brush stimulation after i.t. strychnine, and one became sensitive to brushing over an expanded receptive field. Expansion of the receptive field, as determined by brush stimulation, also was exhibited by all of the low-threshold mechanoreceptive units (14) and wide dynamic range units (2) after i.t. strychnine. The use of air jet stimuli at fixed cutaneous sites also provided evidence of receptive field expansion, because significant unit responses to air jet developed at 13 cutaneous sites (on 7 animals) where an identical stimulus was ineffective in evoking a unit response before i.t. strychnine. However, the magnitude of the unit response to cutaneous air jet stimulation was not changed at sites that already had been sensitive to this stimulus before i.t. strychnine. The onset of allodynia corresponded with the onset of the altered unit responses (i.e., lowered threshold/receptive field expansion) for the majority of animals (9), but the altered unit response either terminated concurrently with symptoms of allodynia (6) or, more frequently, outlasted the symptoms of allodynia (10) as the effects of strychnine declined. The present results demonstrate that the direct, receptor-mediated actions of strychnine on the spinal processing of sensory information are reflected by changes in the receptive fields and response properties of nociceptive and nonnociceptive thalamic neurons. These changes are consistent with the involvement of thalamocortical mechanisms in the expression of strychnine-induced allodynia and, moreover, suggest that i.t. strychnine also produces changes in innocuous tactile sensation.

Animals↗
PubMed1995

Strychnine-dependent allodynia in the urethane-anesthetized rat is segmentally distributed and prevented by intrathecal glycine and betaine.

The blockade of spinal glycine receptors with intrathecal strychnine produces a reversible allodynia-like state in the rat. Thus, hair deflection, in the presence of intrathecal strychnine, induces cardiovascular and motor withdrawal responses comparable with those evoked by noxious thermal, mechanical, or chemical stimulation in the absence of strychnine. In the present study, we mapped the cutaneous sites of abnormal sensitivity to hair deflection throughout the strychnine time course to investigate the segmental distribution of strychnine-induced allodynia. The ability of intrathecal glycine and the glycine derivative betaine to reverse strychnine-induced allodynia was also determined using dose-response analysis. Following intrathecal strychnine (40 micrograms), stroking the legs, flanks, lower back, and tail with a cotton-tipped applicator evoked a pronounced increase in mean arterial pressure, tachycardia, and an abrupt motor withdrawal response in urethane-anesthetized rats. These abnormal responses were only evoked by hair deflection at discrete sites, corresponding to the cutaneous dermatomes innervated by spinal segments near the site of strychnine injection. In rats with intrathecal catheters lying laterally in the subarachnoid space, allodynic sites were observed unilaterally on the ipsilateral side of intrathecal strychnine injection. Recovery from strychnine was complete by 30 min in all affected dermatomes. The cardiovascular and motor withdrawal responses to hair deflection were dose dependently inhibited by intrathecal glycine and intrathecal betaine. The ED50 (95% confidence interval) for intrathecal glycine was 609 (429-865) micrograms for the heart rate response, 694 (548-878) micrograms for the pressor response, and 549 (458-658) micrograms for the motor withdrawal response. The corresponding values for intrathecal betaine were 981 (509-1889), 1045 (740-1476), and 1083 (843-1391) micrograms, respectively. There was no difference in the effect of betaine on sensory-evoked cardiovascular and motor responses. Cortical electroencephalographic activity was not affected by intrathecal glycine or betaine, consistent with a spinal locus of action in reversing strychnine-induced allodynia. These results support the hypothesis that removal of spinal glycinergic modulation from low threshold afferent input with intrathecal strychnine results in segmentally localized, tactile-evoked allodynia.

Anesthetics, Intravenous↗
PubMed1996

Innocuous hair deflection evokes a nociceptive-like activation of catechol oxidation in the rat locus coeruleus following intrathecal strychnine: a biochemical index of allodynia using in vivo voltammetry.

Blockade of spinal glycinergic inhibition with intrathecal (i.t.) strychnine induces a reversible allodynia-like state in both conscious and lightly-anaesthetized rats. Since the locus coeruleus (LC) is activated by noxious stimuli, we determined the effect of non-noxious hair deflection (HD) on noradrenergic neuronal activity in the LC of rats treated with i.t. strychnine. Differential normal pulse voltammetry was used to measure the catechol oxidation current (CA.OC), an index of LC activity. Rats were maintained in a light plane of anaesthesia with i.v. urethane and i.t. strychnine (40 micrograms) was injected near the L1-L2 segment. HD, applied to the caudal dermatomes affected by i.t. strychnine, evoked a significant increase (max. 141 +/- 7%, n = 5, P < 0.05) in CA.OC and mean arterial pressure as compared to baseline (no strychnine). In contrast, HD had no significant effect on CA.OC or mean arterial pressure in the saline-treated rats (n = 5). Pre-treatment with i.t. MK801 (30 micrograms) significantly blocked the increase in CA.OC and mean arterial pressure evoked by HD in strychnine-treated rats. The results of this study indicated that HD, in the presence of i.t. strychnine but not saline, can evoke noradrenergic activity in the LC of lightly anaesthetized rats. This effect on the LC is: (1) comparable to that observed with noxious stimulation without i.t. strychnine; (2) segmentally localized, corresponding to the spinal site of strychnine injection; and (3) mediated by spinal NMDA receptors, consistent with the role of excitatory amino acids in sensory transmission. These data provide the first neurochemical evidence that HD, in the presence of i.t. strychnine, is a nociceptive event, supporting the use of this preparation as an experimental model of allodynia.

Animals↗
PubMed1973

The membrane effects, and sensitivity to strychnine, of neural inhibition of the Mauthner cell, and its inhibition by glycine and GABA.

1. Anionic conductance changes in Mauthner neurones of goldfish were measured during synaptically evoked inhibition and inhibition caused by iontophoretic application of the putative inhibitory transmitters glycine and gamma-aminobutyric acid (GABA).2. The effects of either amino acid were indistinguishable from those of the neural inhibitory transmitter(s). The membrane permeability during the neural or drug response was increased to Br(-), Cl(-), I(-), SCN(-), NO(3) (-), ClO(3) (-), and formate (HCOO(-)), but not to HCO(3) (-), BrO(3) (-), IO(3) (-), SO(4) (-), HPO(4) (-), H(2)PO(4) (-), acetate and citrate.3. Strychnine was injected intramuscularly, iontophoretically, or applied topically to the exposed brain in order to compare quantitatively its ability to prevent inhibition evoked by synaptic activation and by pharmacological means. Inhibitions were measured by the increase in membrane conductance.4. Strychnine, at concentrations just adequate to block completely the late collateral inhibition (LCI) and crossed VIII nerve inhibition, had little effect on the pharmacological inhibition caused by glycine, and sometimes there was no detectable effect at all. In one experiment even a local iontophoretic application of strychnine in a sufficient dose to diffuse over the cell and block the LCI almost completely, merely halved the effect of a small dose of glycine applied to the same localized region of the membrane.5. Higher concentrations of strychnine than those necessary to block synaptically evoked inhibition would reduce the effect of glycine but not that of GABA. The evidence indicated that any apparent effect of strychnine upon GABA could be explained by displacement of the GABA-containing iontophoretic pipette.6. The glycine-blocking action of iontophoretic pulses of strychnine was of relatively very slow onset and long duration compared to the effects of pulses of glycine and GABA.7. These findings can be interpreted as either (1) strychnine has a presynaptic action, preventing the release of inhibitory neurotransmitter, in addition to its less potent post-synaptic one in blocking pharmacological inhibition, or (2) strychnine acts entirely post-synaptically, but the physiological transmitter action differs from that of glycine and GABA in being considerably more sensitive to strychnine antagonism. In either case, the use of strychnine as evidence for the claim that glycine is an inhibitory neurotransmitter at the Mauthner cell is questionable.

Aminobutyrates↗
PubMed1975

Ontogeny of behavioral sensitivity to strychnine in the chick embryo: evidence for the early onset of CNS inhibition.

The development of behavioral sensitivity to strychnine has been studied in the chick embryo between day 7 of incubation and 1 day posthatching. The earliest response to systemically applied strychnine was a marked depression of spontaneous motility at high concentrations of the drug. Lower concentrations had no effect at this time (6-7 days). About 2 days later, on day 81/2 or 9, strychnine induced a statistically reliable increase in spontaneous motility (hyperactivity). This consisted of a brief (i.e. 1-2 min) excitatory response which was followed by a return to baseline activity levels in the case of low drug concentrations, or a depression of activity in the case of low drug concentrations, or a depression of activity in the case of higher concentrations. By 11 days of incubation the brief excitatory response following strychnine had increased in duration to about 4 min. This was also the case for 13-day embryos. At no time between 7 and 13 days were convulsions produced by strychnine, even at concentrations several times greater than that required to induce hyperactivity. For the first time at 16 days myoclonic convulsions were observed following strychnine. These usually began soon after the initial hyperactivity and frequently lasted for as long as 30 min. At the same time the sensitivity of the embryo to strychnine increased, compared to earlier stages. By 18 days strychnine most often induced an immediate convulsive response without the preceding brief hyperactivity. This was also typical of newly hatched chicks. The systemic application of glycine at 9 and 13 days of incubation produced a slight, but statistically reliable, depression of ongoing spontaneous motility, consistent with what one might expect if glycine were acting as an inhibitory neurotransmitter. It typically took between 3 and 4 min following injection for this glycine response to occur. Biochemical, electrophysiological and neuroanatomical evidence was reviewed in an attempt to support the suggestion that the strychnine and glycine data summarized above may reflect the presence of strychnine-sensitive postsynaptic inhibitory processes in the chick spinal cord. Additionally, comparative data on the relative onset of excitatory and inhibitory processes in the developing spinal cord were discussed. It was concluded that, although the data are still imcomplete concerning the question of whether, developmentally, inhibition is a primary or secondary acquisition, inhibitory mechanisms nevertheless appear rather early during vertebrate neurogenesis.

Animals↗
PubMed1991

Site-selective oxidation of strychnine by phenobarbital inducible cytochrome P-450.

The metabolism of strychnine was studied using liver microsomes of rats treated with phenobarbital or 3-methylcholanthrene (MC). The phenobarbital-treatment resulted in 7.9-fold and 4.8-fold increases in 2-hydroxylation and N-oxidation of strychnine, respectively. The formation of 16-hydroxystrychnine, strychnine 21,22-epoxide and 22-hydroxystrychnine was induced about 2-fold. MC-treatment resulted in only 1.4-fold induction of each oxidation activity. In addition, strychnine 2-hydroxylation activity was markedly induced in liver microsomes of phenobarbital-treated mice, guinea pigs, rabbits and dogs (2.5-10.5-fold). Induction of N-oxidation activity was also higher than that of the three other oxidation activities. A reconstituted system of strychnine metabolism using cytochrome P-450 isozymes, P-450I (P450IIB1) and P-450II (P450IIB2), purified from liver microsomes of phenobarbital-treated rats showed significantly high and selective activities towards 2-hydroxylation and N-oxidation of strychnine. This characteristic metabolism of strychnine appears to occur in common with interspecies P450IIB gene subfamily. The pH Optima of 2-hydroxylation and N-oxidation of strychnine were between 8.4 and 8.6 in the microsomes of phenobarbital-treated rats, while that of N-demethylation of benzphetamine, a typical substrate of phenobarbital-inducible cytochrome P-450, was between 7.4 and 7.6. In a reconstituted system with P-450I, strychnine oxidation was little affected by pH change, while benzphetamine N-demethylation activity was decreased in the alkaline side. Among several oxidations tested, only ethylmorphine N-demethylation underwent the same pH effect as did strychnine oxidation with the microsomes and reconstituted system.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Strychnine: a potent competitive antagonist of alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors in rat hippocampal neurons.

In our study, evidence is provided that strychnine, a competitive antagonist at glycine-gated Cl- channels, is also a potent competitive antagonist at native alpha-7-containing, alpha-bungarotoxin-sensitive nicotinic acetylcholine receptor (nAChRs). To address the effects of strychnine on two types of nicotinic responses, the whole-cell mode of the patch-clamp technique was applied to rat hippocampal neurons in culture. Type IA and type II nicotinic currents evoked by acetylcholine (ACh) were inhibited by strychnine in a concentration-dependent manner with IC50S of 1.2 and 38 microM, respectively. Strychnine (2 microM) decreased the peak amplitude of the alpha-bungarotoxin-sensitive type IA current in a voltage-independent manner and prolonged the decay phase of this current. The concentration-response curve for ACh in evoking type IA current showed a parallel shift to the right in the presence of strychnine (2 microM); the EC50 for ACh was increased from 0.4 to 0.8 mM. These findings suggest that strychnine acts as a competitive antagonist of ACh at the alpha 7 nAChRs that subserve type IA current. In contrast, the inhibition by strychnine of type II current was strongly voltage dependent, and the decay phase of this current was markedly accelerated by the toxin, suggesting an open-channel blockade by strychnine of the alpha 4 beta 2 nAChRs subserving type II currents. Preexposure of the neurons to strychnine enhanced its ability to decrease the peak amplitude of type II currents, indicating that the toxin may also act on alpha 4 beta 2 nAChR channels that are not open. It is concluded that strychnine is a potent competitive antagonist of ACh at neuronal alpha 7 nAChRs and a noncompetitive antagonist at the alpha 4 beta 2 nAChR.

Acetylcholine↗
PubMed1996

Involvement of glutamate receptors in strychnine- and bicuculline-induced allodynia in conscious mice.

BACKGROUND: Glycine and gamma-aminobutyric acid (GABA) are inhibitory neurotransmitters that appear to be important in sensory processing in the spinal dorsal horn. Intrathecal administration of strychnine (strychnine-sensitive glycine receptor antagonist) or bicuculline (GABAA antagonist) was reported to induce allodynia. Although the strychnine-induced allodynia was shown to be mediated through the N-methyl-D-aspartate (NMDA)-type glutamate receptor, it is not clear whether the bicuculline-evoked-allodynia is mediated through the glutamate receptor system or how different the allodynia induced by strychnine and bicuculline are. METHODS: Male ddY mice weighing 20 +/- 2 g were used in this study. A 27-G stainless-steel needle attached to a microsyringe was inserted between the L5 and L6 vertebrae by a slight modification of the method of Hylden and Wilcox. Drugs in vehicle were injected slowly into the subarachnoid space to conscious mice at 22 +/- 2 degrees C. The volume of the intrathecal injection was 5 microliters. Studies on allodynia were carried out essentially according to the method of Yaksh and Harty. RESULTS: The intrathecal administration of strychnine or bicuculline in conscious mice resulted in allodynia elicited by nonnoxious brushing of the flanks. The maximum allodynia induced by strychnine was observed 5 min after intrathecal injection, but that induced by bicuculline was observed 10 min after intrathecal injection. Both responses gradually decreased over the experimental period of 50 min. The allodynia induced by strychnine was dose-dependently relieved by NMDA receptor antagonists (D-AP5, ketamine, and 7-C1-KYNA) and non-NMDA receptor antagonists (GAMS and CNQX) but not by metabotropic receptor antagonists (L-AP3 and L-AP4). On the other hand, allodynia induced by bicuculline was dose-dependently relieved by GAMS, L-AP3, and L-AP4, but not by D-AP5, ketamine, 7-C1-KYNA, and CNQX. Whereas the strychnine-evoked allodynia was dose-dependently relieved by the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) and the soluble guanylate cyclase inhibitor methylene blue, the bicuculline-induced one was dose-dependently relieved by methylene blue but not by L-NAME. CONCLUSIONS: These results demonstrate that both strychnine- and bicuculline-evoked allodynia were mediated through pathways that include the glutamate receptor and nitric oxide systems but in a different manner. the current study suggests that GABA and glycine may modulate responses to an innocuous tactile stimulus as inhibitory neurotransmitters at presynaptic and postsynaptic sites in the spinal cord, respectively.

Animals↗
PubMed1999

Spinal action of ketorolac, S(+)- and R(-)-ibuprofen on non-noxious activation of the catechol oxidation in the rat locus coeruleus: evidence for a central role of prostaglandins in the strychnine model of allodynia.

BACKGROUND: Blockade of spinal glycine receptors with intrathecal strychnine produces an allodynia-like state in the anesthetized rat. Innocuous hair deflection in the presence of intrathecal strychnine induces a nociceptive-like activation of catechol oxidation in the locus coeruleus and enhances cardiovascular responses. Because prostaglandins play a central role in augmenting pain, this study evaluated the effect of intrathecal nonsteroidal antiinflammatory drugs in strychnine-induced allodynia. METHODS: In urethane-anesthetized rats, changes in catechol oxidation in the locus coeruleus, measured using in vivo voltammetry, and cardiovascular parameters evoked by hair deflection of caudal dermatomes were determined after strychnine (40 microg) or saline were administered intrathecally. Subsequently, the effects of 30 microg ketorolac, 10 microg S(+)-ibuprofen, and 10 microg R(-)-ibuprofen administered intrathecally were evaluated. RESULTS: After strychnine was administered intrathecally, hair deflection evoked an increase in the locus coeruleus catechol oxidation (peak, 149.7+/-7.2% of baseline) and mean arterial blood pressure (peak, 127.5+/-3.8% of baseline). These responses were not observed after saline was administered intrathecally. All hair deflection-evoked, strychnine-dependent peak responses were attenuated significantly with intrathecally administered ketorolac and S(+)-ibuprofen but not with R(-)-ibuprofen. CONCLUSIONS: Locus coeruleus catechol oxidation is a sensitive biochemical index of strychnine-induced allodynia and is correlated temporally with the cardiovascular responses evoked by hair deflection during spinal glycinergic inhibition. The ability of intrathecally administered ketorolac and S(+)-ibuprofen, but not R(-)-ibuprofen, to suppress the locus coeruleus catechol oxidation and cardiovascular peak responses evoked during strychnine-induced allodynia provide evidence that central prostaglandins play an important role in the abnormal sensory processing of strychnine-induced allodynia.

Anesthesia↗