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P Marek

Publications and source records attributed to P Marek.

At least 19 recordsLinked to original sources
PubMed1999

Design and evaluation of nitrosylated alpha-adrenergic receptor antagonists as potential agents for the treatment of impotence.

We designed and evaluated a new class of molecules, nitrosylated alpha-adrenergic receptor antagonists, as potential agents for the treatment of impotence. In in vitro studies with human and rabbit corpus cavernosum strips in organ chambers, the alpha-adrenergic receptor antagonists (alpha-ARAs) moxisylyte and yohimbine and their corresponding nitrosylated compounds, SNO-moxisylyte (NMI-221) and SNO-yohimbine (NMI-187), concentration-dependently relaxed endothelin-induced contraction. The nitrosylated compounds were significantly more potent than the parent alpha-ARA. In human tissues, the specific phosphodiesterase type 5 inhibitor zaprinast potentiated the relaxing effects of the nitrosylated compounds. Only nitrosylated compounds induced accumulation of cyclic GMP in rabbit corpus cavernosum strips. Yohimbine and NMI-187 demonstrated a potent alpha2-blocking activity, with no significant differences in pA2 values (8.9 versus 8.2, respectively). Moxisylyte and NMI-221 showed moderate potency in antagonizing phenylephrine contraction, with comparable pA2 values for both molecules (6.5 versus 6.6, respectively). alpha-Adrenergic receptor-binding studies showed similar binding affinities for the alpha-ARA and their corresponding nitrosylated compounds. In vivo, intracavernosal injection of nitrosylated molecules caused greater increases in intracavernosal pressure (NMI-221 versus moxisylyte) that were more long lasting than those of moxisylyte or yohimbine. There were no significant differences between nitrosylated and non-nitrosylated compounds in the magnitude of systemic mean arterial pressure decrease after intracavernosal injection. alpha-ARA and the nitrosylated compounds showed no pain-inducing activity as evaluated with the paw-lick model in mice. In summary, nitrosylated alpha-ARA have the dual functionalities of nitric oxide donors and alpha-ARA. These drugs induced penile erection in animals, suggesting their possible therapeutic value as agents for the local pharmacological treatment of impotence.

Adrenergic alpha-Antagonists↗
PubMed1998

[Kearns-Sayre syndrome].

The authors describe a rare group of symptoms, resulting in progressive external ophthalmoplegia, retinal pigment epithelial dysfunction and cardiac conduction disturbance. The illness belongs to the group of mitochondrial cytopathies. The case extends over the diagnostic possibilities, with special attention on electromyographic diagnostic, clinical symptoms, pathomechanism of the disease, and the therapic possibilities.

Aged↗
PubMed1997

Neuroprotective activity of a new class of steroidal inhibitors of the N-methyl-D-aspartate receptor.

Release of the excitatory neurotransmitter glutamate and the excessive stimulation of N-methyl-D-aspartate (NMDA)-type glutamate receptors is thought to be responsible for much of the neuronal death that occurs following focal hypoxia-ischemia in the central nervous system. Our laboratory has identified endogenous sulfated steroids that potentiate or inhibit NMDA-induced currents. Here we report that 3alpha-ol-5beta-pregnan-20-one hemisuccinate (3alpha5betaHS), a synthetic homologue of naturally occurring pregnanolone sulfate, inhibits NMDA-induced currents and cell death in primary cultures of rat hippocampal neurons. 3alpha5betaHS exhibits sedative, anticonvulsant, and analgesic properties consistent with an action at NMDA-type glutamate receptors. Intravenous administration of 3alpha5betaHS to rats (at a nonsedating dose) following focal cerebral ischemia induced by middle cerebral artery occlusion significantly reduces cortical and subcortical infarct size. The in vitro and in vivo neuroprotective effects of 3alpha5betaHS demonstrate that this steroid represents a new class of potentially useful therapeutic agents for the treatment of stroke and certain neurodegenerative diseases that involve over activation of NMDA receptors.

Animals↗
PubMed1996

The neuroprotective efficacy of MK-801 in focal cerebral ischemia varies with rat strain and vendor.

The present study was designed to evaluate whether the neuroprotective efficacy of MK-801 in focal cerebral ischemia was dependent on strain and/or vendor differences. MK-801 (0.12 mg/kg i.v. bolus followed by 0.108 mg/kg/h infusion or 0.60 mg/kg i.v. bolus followed by 0.540 mg/kg/h infusion) or saline was administered just after intraluminal middle cerebral artery occlusion. Administration of 0.540 mg/kg/h MK-801 provided strain/line-dependent neuroprotection in the following rank order: Simonsen Laboratories Sprague-Dawley rats > Simonsen Laboratories Wistar rats > Taconic Laboratories Sprague-Dawley rats. After 0.108 mg/kg/h MK-801 treatment, Simonsen Laboratories Wistar rats were the only strain/line that were significantly neuroprotected. These results indicate that the neuroprotective effect of an experimental drug may be influenced by rat strain and vendor differences.

Animals↗
PubMed1996

The genetics of pain and pain inhibition.

The present review summarizes the current state of knowledge about the genetics of pain-related phenomena and illustrates the scope and power of genetic approaches to the study of pain. We focus on work performed in our laboratories in Jastrzebiec, Poland; Portland, OR; and Los Angeles, which we feel demonstrates the continuing usefulness of classical genetic approaches, especially when used in combination with newly available molecular genetic techniques.

Analgesia↗
PubMed1996

Differential sensitivity of mice bred for stress-induced analgesia to morphine and ACEA-1011 in the formalin test.

The antinociceptive effect of morphine, an opioid receptor agonist, and ACEA-1011, a novel NMDA receptor/glycine site antagonist, was examined in the formalin test in mice selectively bred for high (HA) and low (LA) swim stress-induced analgesia (SSIA). A subcutaneous (SC) injection of formalin produced a biphasic nociceptive response in both lines. HA mice spent more time licking the injected paw than the LA mice in both phases of the formalin test. Morphine was equally potent in the early phase in both lines, but it was more potent in HA mice than in LA mice in the tonic late phase of the formalin test. Similarly, ACEA-1011 produced an equally potent antinociceptive effect in the early phase in both lines; however, the compound was more potent in LA mice than in HA mice in the tonic late phase of the formalin test. These data suggest that in HA mice antinociception in the tonic late phase of the formalin test is mediated largely by an opioid-mediated mechanism, whereas in the opioid-deficient LA line at least a nonopioid-mediated mechanism involving the NMDA receptor is also implicated.

Analgesia↗
PubMed1995

Infarct volume varies with rat strain and vendor in focal cerebral ischemia induced by transcranial middle cerebral artery occlusion.

We recently reported that the outcome of focal cerebral ischemia induced by intraluminal middle cerebral artery occlusion may differ depending upon a rat's strain and/or vendor. Sprague-Dawley rats originating from Taconic Laboratories and Charles River Laboratories had infarct volumes several fold larger than Sprague-Dawley rats originating from Simonsen Laboratories. The present study sought to determine whether these differences were restricted to an intraluminal technique or whether strain and vendor dependent differences will also exist in rats subjected to a transcranial method of focal cerebral ischemia. Accordingly, we permanently coagulated the middle cerebral artery via a transcranial approach in Sprague-Dawley rats originating from Simonsen Laboratories and Taconic Laboratories and in Simonsen Laboratories Fischer-344 rats. The cortical infarct volume significantly differed in the following order: Simonsen Laboratories Sprague-Dawley rats < Simonsen Laboratories Fischer-344 rats < Taconic Laboratories Sprague-Dawley rats. The subcortical infarct volume differed statistically in the following order: Simonsen Laboratories Sprague-Dawley rats < Taconic Laboratories Sprague-Dawley rats < Simonsen Laboratories Fischer-344 rats. These results along with our previous findings demonstrate that strain and vendor differences in the outcome of focal cerebral ischemia are independent of the technique applied.

Animals↗
PubMed1995

The role of strain/vendor differences on the outcome of focal ischemia induced by intraluminal middle cerebral artery occlusion in the rat.

This study investigated the role of strain and vendor differences on the outcome of focal cerebral ischemia in the rat induced by occlusion of the middle cerebral artery by an intraluminal thread. The cortical infarct volumes (Mean +/- S.E.M.) were: 14.2 +/- 6.2 mm3 in Simonsen Laboratories Sprague-Dawley rats; 84.0 +/- 22.9 mm3 in Simonsen Laboratories Wistar rats; 223.3 +/- 23.6 mm3 in Taconic Laboratories Sprague-Dawley rats; and 239.5 +/- 30.7 mm3 in Charles River Laboratories Sprague-Dawley rats. Middle cerebral artery occlusion combined with bilateral common carotid artery occlusion for 60 min increased cortical infarct volumes to: 113.0 +/- 18.8 mm3; 152.4 +/- 21.1 mm3; 227.8 +/- 19.3 mm3; and 248.4 +/- 24.0 mm3, respectively. To control the effect of blood pressure as a variable contributing to the outcome of ischemia, additional experiments where performed in which the blood pressure in Simonsen Laboratories Sprague-Dawley rats was lowered to the level of the blood pressure in Taconic Laboratories Sprague-Dawley rats. Although this manipulation increased the cortical infarct volumes in Simonsen Laboratories Sprague-Dawley rats, the volumes were still less than those in Taconic Laboratories Sprague-Dawley rats. The results of the present study indicate that the outcome of ischemia in the intraluminal thread model may dramatically differ depending on the strain and vendor of animal used.

Animals↗
PubMed1994

Mu-opiate receptor binding is up-regulated in mice selectively bred for high stress-induced analgesia.

Pain perception and sensitivity to opiate analgesics strongly depend on genotype. Mice selectively bred for high (HA) and low (LA) swim stress-induced analgesia display markedly divergent morphine analgesia, a difference that appears to be determined by one or at the most two major genes. In an attempt to provide candidate genes mediating the supranormal analgesia displayed by HA mice, we performed mu-opiate receptor binding on 27th generation HA, LA, and control (C) mice using [3H]naloxone. HA mice were found to have significantly higher whole-brain receptor density (Bmax) than LA mice in whole brain homogenates; no significant difference in affinity (Kd) was observed. Quantitative autoradiography confirmed the line difference in whole-brain receptor binding. In the medial thalamus, a brain area implicated in ascending pathways of pain inhibition, HA mice were found to display significantly higher [3H]naloxone binding than C mice (a 64% increase) and LA mice (a 128% increase). No significant line differences were observed in any other brain locus. Thalamic mu receptors may therefore play an important role in a central 'volume control' mechanism of pain inhibition, and underlie individual differences in the responses of mice to opiate analgesic drugs.

Analgesia↗
PubMed1993

Morphine fails to produce tolerance when administered in the presence of formalin pain in rats.

The present study examined the development of tolerance to morphine analgesia under conditions in which morphine was administered in the presence or absence of pain induced by subcutaneous injection of 50 microliters of 2.5% formalin into the hind paw of rats. Animals were injected with morphine (25 mg/kg, i.p.) or saline for 3 consecutive days either in the presence of pain (10 min after formalin injection) or in the absence of pain (6 h prior to formalin injection). On the 4th day, tolerance to the analgesic effect of test doses of morphine (6 or 10 mg/kg) was assessed in the formalin and tail-flick tests, respectively. Significant tolerance in both tests was observed in animals receiving morphine in the absence of pain during the tolerance induction period, but not in animals receiving morphine in the presence of pain.

Animals↗
PubMed1993

NMDA receptor antagonists, MK-801 and ACEA-1011, prevent the development of tonic pain following subcutaneous formalin.

Subcutaneous injection of formalin produces a biphasic pain response: an early, transient phase followed by a late tonic phase. The present study examined the involvement of the N-methyl-D-aspartic acid (NMDA) receptor in the development of the late pain produced following subcutaneous injection of formalin into the hind paw in mice. Blockade of the NMDA receptor by its non-competitive antagonist, MK-801, prior to formalin injection, but not after, reduced pain during the late phase. Similarly, blockade of the NMDA receptor allosteric site by the novel glycine site antagonist, ACEA-1011, also reduced the pain response in the late phase. These results suggest that the development of the late phase of formalin pain is due to NMDA-mediated activity during the early phase.

Analgesics↗
PubMed1993

Levorphanol and swim stress-induced analgesia in selectively bred mice: evidence for genetic commonalities.

Two independent selective breeding programs have developed divergent lines of mice expressing either high and low swim stress-induced analgesia (HA/LA lines; Jastrzebiec, Poland) or high and low levorphanol analgesia (HAR/LAR lines; Portland, OR). In the present study, mice from both programs were tested for both levorphanol analgesia (2 mg/kg) and an opioid-mediated swim stress-induced analgesia (3 min swimming in 32 degrees C water) in the hot-plate test. Mice selected for high and low levorphanol analgesia displayed high and low swim stress-induced analgesia, respectively; mice selected for high and low swim stress-induced analgesia displayed high and low levorphanol analgesia, respectively. This pattern of correlated responses suggests a high degree of common genetic determination in opiate and swim stress-induced analgesia. These findings also suggest that individual differences in analgesic responsiveness to opiate drugs result from genetically determined individual differences in endogenous pain inhibitory mechanisms.

Analgesia↗
PubMed1993

Antagonism of the non-opioid component of ethanol-induced analgesia by the NMDA receptor antagonist MK-801.

Recent evidence from our laboratory suggests that the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine) selectively antagonizes non-opioid (i.e. naloxone-insensitive) mechanisms of stress-induced analgesia in mice. For example, we have recently demonstrated that a low dose of MK-801 (0.075 mg/kg, i.p.) antagonizes the non-opioid component of a mixed opioid/non-opioid swim stress-induced analgesia (SSIA) resulting from forced swimming for 3 min in 20 degrees C water. Since ethanol-induced analgesia (EIA) has been found to be only partially attenuated by naloxone, we hypothesized that MK-801 would similarly block the non-opioid component of EIA. The effects of MK-801 and of the opioid receptor antagonist naloxone (10 mg/kg, i.p.) on analgesia produced by ethanol (2.5 g/kg in 20% vol/vol, i.p.) were studied in control mice and in mice selectively bred for high (HA) or low (LA) SSIA. HA mice showed significantly more, and LA mice significantly less, EIA than controls. Naloxone and MK-801 significantly attenuated EIA in control and HA mice, and in these lines the combined administration of both antagonists blocked EIA completely. In LA mice, which displayed very little EIA, naloxone but not MK-801 reversed EIA completely. These findings provide additional evidence for the role of the NMDA receptor in non-opioid mechanisms of analgesia. The finding that mice selectively bred for high and low SSIA, also display high and low EIA suggests common mediation of the effects of stress and ethanol on antinociceptive processes.

Analgesia↗
PubMed1992

The specific N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 blocks U-50,488, but not morphine antinociception.

The effect of the specific NMDA receptor antagonist MK-801 on antinociception produced by the kappa opiate receptor agonist U-50,488 and the mu receptor agonist morphine was assessed using the tail-flick test in rats. MK-801 (0.05 and 0.1 mg/kg) antagonized antinociception induced by all three doses of U-50,488 (7.5, 15 and 30 mg/kg), and potentiated antinociception induced by the lower (1 mg/kg) but not higher (5 mg/kg) dose of morphine. Naloxone at a dose of 1.0 but not 0.1 mg/kg blocked U-50,488 antinociception, indicating that MK-801 affects opiate antinociception. The present results are the first to suggest a critical role for the NMDA receptor in opiate antinociception involving the kappa receptor.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1992

N-methyl-D-aspartic acid (NMDA) receptor antagonist MK-801 blocks non-opioid stress-induced analgesia. II. Comparison across three swim-stress paradigms in selectively bred mice.

The effects of the specific N-methyl-D-aspartic acid (NMDA) receptor antagonist MK-801 (dizocilpine, 0.075 mg/kg, i.p.) on swim-stress-induced analgesia (SSIA) were studied in control (C) mice and in mice selectively bred for high (HA) or low (LA) SSIA. In three consecutive experiments, animals were subjected to forced swimming at water temperature of 20 degrees C, 32 degrees C and 15 degrees C and the resulting analgesia (hot-plate test) was found to be mixed opioid/non-opioid, opioid and non-opioid, respectively, as a function of the degree of antagonism by naloxone (10 mg/kg, i.p.). The major finding of this study is that MK-801 attenuated 15 degrees C SSIA, against which naloxone was ineffective, but had no effect on 32 degrees C SSIA, which naloxone blocked completely. A combination of naloxone and MK-801 significantly attenuated 20 degrees C SSIA in C and HA mice and in HA mice this attenuation was significantly larger than that produced by either drug alone. Morphine analgesia (10 mg/kg, i.p.) was unaffected by MK-801. It is concluded that low doses of MK-801 selectively block non-opioid mechanisms of SSIA.

Analgesia↗
PubMed1992

The NMDA receptor antagonist MK-801 prevents long-lasting non-associative morphine tolerance in the rat.

Several studies have demonstrated that the N-methyl-D-aspartate (NMDA) antagonist MK-801 attenuates the development of morphine tolerance and withdrawal. These studies employed repeated morphine injections to induce tolerance, a procedure in which learning has been suggested to play a significant role in tolerance development. MK-801 has been reported to block some types of learning, and it is unclear, therefore, whether the effect of MK-801 on tolerance development is due to its antagonism of associative (learning) or non-associative factors. Moreover, previous studies have tested the effects of MK-801 on morphine tolerance only up to 48 h after its induction; yet morphine tolerance can persist for many months, and it is not known whether MK-801 can block long-lasting tolerance. In the present study, therefore, we adopted a model of morphine tolerance in which the involvement of learning is minimized by using a single injection of morphine in a sustained-release preparation, and we tested tolerance for up to 56 days. In the first experiment, simultaneously administering MK-801 (0.2 mg/kg, s.c.) and morphine (60 mg/kg, s.c.), each in a sustained-release preparation, abolished tolerance that lasted at least 12 days. Analgesia was measured in the hot-plate test following a test dose of morphine (15 mg/kg, i.p.). In the second experiment, delivering MK-801 and morphine as before, the duration of morphine-induced catalepsy and analgesia was prolonged. Nevertheless, 24 h later one symptom of naloxone-precipitated withdrawal was significantly attenuated in these same animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗