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ABSTRACT: Gene-environment interactions have an important role in the development of psychiatric disorders. To generate and validate a new substrain of rats with signs related to schizophrenia, we used selective breeding after postweaning social isolation and chronic ketamine treatment through several generations of animals and compared the subsequent strain to naive rats that were not genetically manipulated. We further investigated whether social isolation and ketamine treatment augmented the appearance of schizophrenic-like signs in these rats. Four experimental groups were studied (n=6-15 rats/group): naive rats without any treatment (NaNo); naive rats with postweaning social isolation and ketamine treatment (NaTr); 15(th) generation of selectively bred animals without any treatment (SelNo) or selectively bred rats with both isolation and ketamine treatment (SelTr). The startle reaction, tail-flick and novel object recognition tests were used to classify the animals into low- or high-risk for schizophrenia. Reduced pain sensitivity, higher degree of the startle reaction, disturbed prepulse inhibition, altered motor activity and decreased differentiation index in the memory test were observed in the 15(th) generation of the substrain, along with enhanced grooming behavior. Five functional indices (TF latency, startle reaction, prepulse inhibition, differentiation index, and grooming activity) were rated from 0 - 2, and the analysis of the summarized score revealed that the NaNo group had the lowest overall indication of schizophrenic-like signs, while the SelTr animals scored the highest, suggesting that both heritable and environmental factors were important in the generation of the behavioral alterations. We assume that further breeding after this complex treatment may lead to a valid and reliable animal model of schizophrenia.
Behavioural brain research 11/2012; · 3.22 Impact Factor
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ABSTRACT: While it is well known that the endogenous cannabinoid receptor ligand anandamide also activates the transient receptor potential vanilloid1 (TRPV1) receptors, there has been no in vivo study indicating the role of the TRPV1 receptors in the antinociceptive effect of anandamide at spinal level. The goal of this study was to determine the effect of inhibition of TRPV1 receptors by capsazepine on the antinociceptive potency of anandamide after intrathecal administration. Anandamide alone (1, 30 or 100 microg) dose-dependently decreased carrageenan-induced thermal hyperalgesia, however, the highest dose caused temporary excitation and vocalization, suggesting the pain-inducing potential of anandamide. Capsazepine (10 or 20 microg) by itself did not change the pain sensitivity markedly, but the lower dose increased it, and the higher dose decreased the antinociceptive effect of 30 microg anandamide. Furthermore, both doses of capsazepine decreased the efficacy of the largest dose of anandamide. These results show that TRPV1 receptor activation plays a substantial role in the antinociceptive effects of anandamide at spinal level. The effect of the inhibition on TRPV1 receptors depended on the dose applied. We presume that coactivation of the cannabinoid and TRPV1 receptors by anandamide provides elevated antinociception through the release of antinociceptive endogenous ligands at spinal level.
Pain 03/2008; 134(3):277-84. · 5.78 Impact Factor
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ABSTRACT: A very interesting and rapidly developing field of pain research is related to the roles of different endogenous ligands. This study determined the antinociceptive interactions of triple and quadruple combinations of different endogenous ligands (endomorphin-1, adenosine, agmatine and kynurenic acid) on carrageenan-induced inflammatory pain model at the spinal level. Intrathecal infusion (60 min) of these drugs alone, in double, triple or quadruple combinations, was followed by a 60-min observation period. During the infusion, antihyperalgesic effect of 0.3 microg/min endomorphin-1 was higher in the triple combinations than those in the double combinations. After cessation of drug administration, only the combination of 0.3 microg/min endomorphin-1, 1 microg/min agmatine, and 0.3 microg/min adenosine was more effective than the double combinations. In quadruple combinations, the antinociceptive effects of both 0.1 and 0.3 microg/min endomorphin-1 were significantly potentiated by the otherwise ineffective triple combination of adenosine, agmatine, and kynurenic acid. No side effects could be observed at these doses. These results demonstrate that triple and quadruple combinations of these endogenous ligands caused more effective antihyperalgesia compared with double combinations. Accordingly, the doses of these substances could be further reduced, thus, reinforcing the view that complex activation and/or inhibition of different systems can be sufficiently effective in blocking nociception without adverse effects. Because all of these drugs had effects on various receptors and systems, the possible types of these interactions were discussed.
Brain Research 07/2007; 1155:42-8. · 2.73 Impact Factor
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ABSTRACT: It is well known that a multitude of transmitters and receptors are involved in the nociceptive system, some of them increasing and others inhibiting the pain sensation both peripherally and centrally. These substances, which include neurotransmitters, hormones, etc., can modify the activity of nerves involved in the pain pathways. Furthermore, the organism itself can express very effective antinociception under different circumstances (e.g. stress), and, during such situations, the levels of various endogenous ligands change. A very exciting field of pain research relates to the roles of endogenous ligands. Most of them have been suggested to influence pain transmission, but only a few studies have been performed on the interactions of different endogenous ligands. This review focuses on the results of antinociceptive interactions after the co-administration of endogenous ligands. The data based on 55 situations reveal that the interactions between the endogenous ligands are very different, depending on the substances, the pain tests, the species of animals and the route of administrations. It is also revealed that only a few of the possible interactions between endogenous ligands have been investigated to date, in spite of the fact that the type of antinociceptive interaction between different endogenous ligands could hardly be predicted. The results indicate that the combination of endogenous ligands should not be omitted from the pain therapy arsenal. Attention will hopefully be drawn to the complex interdependence of endogenous ligands and their potential use in clinical practice.
Brain Research Reviews 09/2006; 52(1):69-92. · 10.34 Impact Factor
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ABSTRACT: Acute tolerance develops after a single administration of opiate or alpha(2)-adrenergic agonists, but the characteristics of the delayed type of acute tolerance have not been analyzed in acute and inflammatory thermal pain tests. We investigated the long-term changes in the antinociceptive potency of morphine (10 mg/kg) injected intraperitoneally and the alpha(2)-adrenoceptor agonist dexmedetomidine (150 microg/kg intraperitoneally) on acute heat pain (tail-flick test) sensitivity and on carrageenan-induced inflammatory thermal hyperalgesia (paw withdrawal test) after a second injection 7 days later. The first treatment did not influence the baseline values on Day 8 in either test. In the tail-flick test, the antinociceptive potency of morphine, but not that of dexmedetomidine, was significantly decreased after repeated administration, suggesting a delayed type of acute tolerance to morphine. In contrast, the antihyperalgesic effect of morphine in the paw withdrawal test did not change after repeated injection, whereas the potency of dexmedetomidine was increased on Day 8. There were significant differences between the inflamed and noninflamed sides on Day 1 but not on Day 8, revealing an increased potency of the drugs on the inflamed side. There was no sign of cross-tolerance between the two drugs in either pain test. These data indicate long-term changes in the antinociceptive potency of morphine or dexmedetomidine after single treatment in different heat pain tests.
Anesthesia & Analgesia 10/2005; 101(3):812-8, table of contents. · 3.29 Impact Factor
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ABSTRACT: Adenosine, agmatine and kynurenic acid are endogenous ligands acting on different (e.g. adenosine, NMDA, alpha(2)-adrenergic and imidazoline) receptors with a potential role in nociception at the spinal level. Their antinociceptive effects have already been investigated as monotherapy, but only a few studies have reported on their effects on the potency of other drugs. The purpose of the present study was carried out to analyse their interactions during continuous intrathecal co-administration in a carrageenan-induced thermal hyperalgesia model in rats. A paw withdrawal test was used for nociceptive testing. The intrathecal infusion (60 min) of these three drugs was administered alone or in combinations (kynurenic acid+adenosine or agmatine; adenosine+agmatine), which was followed by an additional 60-min observation period. Kynurenic acid alone was ineffective, while adenosine and agmatine alone caused a slight increase in pain threshold. However, independently of the applied doses all of the combinations significantly (p<0.05) increased the paw withdrawal latencies on the inflamed side during and after the infusion, but were almost ineffective on the normal side. The adenosine+kynurenic acid combination was the most effective: namely, that it relieved thermal hyperalgesia in all the applied dose combinations. Treatment with the kynurenic acid-containing combinations also caused dose-dependent side-effects (motor impairment and excitation), despite the fact that monotherapy with kynurenic acid in the applied dose (0.1 microg/min) did not result in adverse effects.
Brain Research 12/2004; 1029(1):93-102. · 2.73 Impact Factor
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ABSTRACT: Recently, a series of endogenous ligands related to inhibition of sensory transduction of noxious stimuli at the spinal level has been described, including endomorphins, agmatine, and adenosine, which act on different receptors; however, little data exist concerning their effect during continuous administration or their interactions. In this study, we investigated the antinociceptive properties of continuously administered (for 60 min) adenosine and agmatine on carrageenan-induced thermal hyperalgesia by means of a thermal paw withdrawal test in awake rats. The possible interaction between endomorphin-1 and adenosine or agmatine was also determined. Continuous administration of adenosine (0.3-3 microg/min) did not influence the paw withdrawal latencies of the normal or inflamed paws during the infusion but in larger doses it resulted in a significant increase in latencies after the cessation of the infusion. Agmatine (0.3-3 microg/min) dose-dependently decreased the hyperalgesia, but the largest dose caused a temporary excitation in 50% of animals. The continuous administration of adenosine or agmatine (3 micro g/min) potentiated and prolonged the antinociceptive effect of endomorphin-1 (1 microg/min). Our results revealed that adenosine and agmatine have a small antinociceptive efficacy during continuous intrathecal administration but that both potentiate the effect of endomorphin-1. These data suggest that the combination of these endogenous ligands might represent novel targets for the therapeutic modulation of pain; however, the systematic examination of side effects is essential. IMPLICATIONS: Adenosine and agmatine have little antinociceptive efficacy during continuous intrathecal administration, as shown by the inflammatory pain test in rats, but both potentiate the effect of endomorphin-1. These data suggest that the combination of these endogenous ligands might represent novel targets for the therapeutic modulation of pain; however, the systematic examination of side effects is essential.
Anesthesia & Analgesia 03/2004; 98(2):420-6, table of contents. · 3.29 Impact Factor
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ABSTRACT: The extract of Sempervivum tectorum L. (Crassulaceae) containing several flavonoids is widely used as an antiinflammatory agent in folk medicine. Previous studies have demonstrated that various flavonoids or flavonoid-containing plant extracts produce significant antinociception, but no data are available concerning their antinociceptive effect especially at the spinal level. The purpose of the present study was to investigate the antinociceptive activity of Sempervivum tectorum L. extract on acute and inflammatory pain sensitivity in awake rats. The pain sensitivity was assessed by the acute tail- flick test in intact rats and by the paw withdrawal test after carrageenan-induced inflammation using heat stimulus. The plant extract was administered intraperitoneally and intrathecally in rats. The intraperitoneal injection of a high dose of the extract (1000 mg/kg) significantly (p < 0.05) increased the paw withdrawal latency of the inflamed paw. The intrathecal administration (30-300 micro g) caused a small, but significant increase (10%-15%) in tail- flick latency. In the carrageenan-induced inflammatory model, the intrathecally applied extract (30-1000 micro g) significantly decreased, but did not relieve the thermal hyperalgesia. The results suggest that the spinal cord does not seem to play an important role in the antinociceptive effects of this plant extract.
Phytotherapy Research 11/2003; 17(9):1032-6. · 2.09 Impact Factor
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ABSTRACT: Although chronic intrathecal catheterization is a widely used method in rats, few calibration experiments have been performed. In this study, we investigated the correlation between the side position of the catheter tip and the side differences observed in the motor and sensory disturbances after intrathecal administration of lidocaine to a large number of rats. The existence of a sensory block was determined by the paw withdrawal test. The motor impairment was assessed by observing the complete clubbing of the hindpaw and measuring the hindpaw grip strength. After experimental use, we established the position of the catheter tip. The catheter tips were variously located in all directions of the transverse plane in the rat spinal subarachnoid space. Lidocaine administration (100 or 500 microg/5 microL; n = 264 and 112, respectively) led to dose-dependent motor and sensory disturbances. The effect of 100 microg of lidocaine exhibited side differences; i.e., the extents of both motor (r = 0.77) and sensory (r = 0.60 and r = 0.67 for the right and the left side, respectively) disturbances correlated significantly with the location of the catheter tip. Our data have shown that detection of the paralytic and/or antinociceptive effect of small-dose lidocaine before planned experiments is a simple and reliable method for prediction of the location of the catheter tip. We suggest that the position of the catheter might cause side differences in the drug effect, especially if small doses of drugs are administered and their effects are investigated on both sides.
Anesthesia & Analgesia 03/2003; 96(2):487-92, table of contents. · 3.29 Impact Factor
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ABSTRACT: Kynurenic acid as an endogenous ligand antagonizes all types of ionotropic glutamate receptors, with preferential affinity for the glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor. The purpose of the present study was to investigate the antinociceptive potency of continuously administered kynurenic acid on carrageenan-induced thermal hyperalgesia by means of a paw withdrawal test in awake rats. The possible interaction between kynurenic acid and the endogenous mu-opioid receptor agonist peptide, endomorphin-1, was examined in the same set-up. Kynurenic acid at the higher doses (1-4 microg/min) significantly decreased the thermal hyperalgesia and increased the paw withdrawal latencies on the non-inflamed side. These doses were also associated with motor impairment on both sides. Low doses of kynurenic acid (0.01-0.1 microg/min) potentiated, but did not prolong, the antinociceptive effect of endomorphin-1 (0.1-1 microg/min) on the inflamed side. There was no sign of motor impairment during the combined treatment. These findings demonstrate that the combination of low doses of these two endogenous ligands provides effective and well-controlled antinociception without side effects.
European Journal of Pharmacology 07/2002; 445(1-2):93-6. · 2.52 Impact Factor
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ABSTRACT: 1. Chronic pain owing to arthritis is a major clinical problem worldwide. To study the underlying pathological mechanisms of chronic pain and the effectiveness of different treatments, a number of experimental models have been developed over the years. 2. We introduced a new subchronic inflammatory model by repeated unilateral administration of carrageenan into the ankle joint of rats, and investigated the degree and the time-course of the oedema, and thermal and mechanical hyperalgesia. 3. Carrageenan (450 microg) was injected on three occasions (on days 1, 4 and 7), and the resulting oedema, thermal hyperalgesia (paw withdrawal test) and weight load were characterized in voluntarily walking rats daily for 15 days. The effect of diclofenac sodium (3 mg/kg orally daily for 15 days) was also determined. 4. Repetitive administration of carrageenan caused fluctuating oedema and pain responses, which did not normalize within 3 days. Exacerbated inflammatory oedema was observed after the second and third injections. Oedema and a decreased weight load of the inflamed paw were observed throughout the investigation period, and paw withdrawal thresholds to noxious thermal stimuli returned to baseline pre-carrageenan values from Day 13. 5. Oral diclofenac (3 mg/kg daily for 15 days) significantly decreased oedema within a few days (Day 3), whereas its anti-allodynic effect developed only several days later (Day 9). However, diclofenac at the applied dose did not influence the thermal hyperalgesia. 6. The results suggest that the repeated administration of carrageenan might be a suitable model for determining the effects of long-lasting treatment.
Clinical and Experimental Pharmacology and Physiology 34(5-6):520-6. · 1.85 Impact Factor
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ABSTRACT: Both anandamide and adenosine have significant roles in pain mechanisms, but no data are available concerning their interaction at the spinal level. The goal of this study was to determine how adenosine and the adenosine receptor antagonist caffeine affect the antinociceptive effect of anandamide.The pain sensitivity was assessed by the acute tail-flick test and by paw withdrawal test after carrageenan-induced inflammation. The substances were administered intrathecally to male Wistar rats.Anandamide alone (1, 30 and 100 μg) dose-dependently decreased the hyperalgesia, however it had low potency in the tail-flick test. Neither adenosine (100 μg) nor caffeine (400 μg) alone changed the pain sensitivity markedly. Their combination caused a short-lasting antihyperalgesia, but it did not influence the tail-flick latency. Both adenosine and caffeine decreased the antihyperalgesic potential of 100 μg anandamide, while adenosine–caffeine pretreatment temporarily enhanced its effect. As regards acute heat pain sensitivity, no combination with anandamide influenced the effect of anandamide.These findings provide new data concerning the interaction between two endogenous ligands and caffeine. Since these substances may exert effects on several receptors and/or systems, their interaction in vivo must be very complex and the net outcome after their coadministration could not been predicted from the in vitro results.
Pharmacology Biochemistry and Behavior.
