Theo Meert - Academia.edu (original) (raw)
Papers by Theo Meert
Behavioural Pharmacology, 1992
Rats given a subchronic cocaine treatment for 10 days display an inhibition of exploratory behavi... more Rats given a subchronic cocaine treatment for 10 days display an inhibition of exploratory behaviour 24h after the last cocaine treatment in the open field test. As compared to the vehicle controls, the exploratory inhibition could be measured in terms of a longer latency to enter the open area, a reduction in the time spent in the open field and a decrease in the number of transits from the small dark compartment into the open area. The serotonin (5-HT(2/1C)) antagonist ritanserin, given subcutaneously 1h prior to testing, overcame this behavioural inhibition. At doses between 0.04mg/kg and 10.0mg/kg ritanserin, a complete normalization of exploratory activity was obtained. In chronic vehicle treated rats, ritanserin did not increase exploration. Therefore the effects of ritanserin cannot be attributed to a general activation. The results are discussed with regard to withdrawal anxiety and a possible therapeutic role of ritanserin in drug addicts.
Pharmacology Biochemistry and Behavior, Aug 1, 2007
The primary aim of the study was to describe and correlate pain behavior and changes in bone morp... more The primary aim of the study was to describe and correlate pain behavior and changes in bone morphology in animal models of arthritis both in rats and guinea pigs. Either complete Freund's adjuvant (CFA) or mono-iodoacetate (MIA) solution was injected into the left knee joint to obtain a model for rheumatoid arthritis and osteoarthritis, respectively. Subsequently, animals were behaviorally tested during a period of 12 days after CFA injection and at least 19 days after MIA injection. During these observation periods increasing pain behavior was observed, characterized by decreased von Frey mechanical thresholds and weight bearing on the affected limb. In Hargreaves' paw flick test slightly increased thermal hypersensitivity was observed in some instances in guinea pigs. In rats there was also decreased limb-use during forced ambulation. To evaluate bone destruction mu-computed tomography scans of the arthritic knee were taken on the last experimental day. Different bone parameters indicative of osteolysis and decreased trabecular connectivity were significantly correlated with the observed pain behavior. Detailed description of morphological changes in arthritic joints better characterizes the different animal models and might add to the knowledge on the working mechanisms of analgesic compounds that have an influence on bone structures in arthritis.
Drug Development Research, 1992
Meert, T.F., and P.A.J. Janssen: Ritanserin, a new therapeutic approach for drug abuse.
Bioorg Medicinal Chem Letter, 2006
A novel series of 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives has been prepared and thei... more A novel series of 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives has been prepared and their synthesis described herein. In vitro affinities for δ-, μ-, and κ-opioid receptors, as well as the functional activity in the [35S]GTPγS assay are reported. The most potent and selective δ-opioid agonist 18a exhibited a Ki of 18 nM, and was >258-fold and 28-fold selective over μ- and κ-receptors, respectively; the compound is a full agonist with an EC50 value of 14 nM.A new chemical class of selective δ-opioid agonists based on the 4-phenyl-4-[1H-imidazol-2-yl]-piperidine scaffold is reported. A highly selective δ agonist (18a, EC50 = 14 nM) was identified.
Behavioural Brain Research, Mar 17, 2010
Two voltage gated sodium channels, Na v 1.8 and Na v 1.9, are exclusively expressed in primary se... more Two voltage gated sodium channels, Na v 1.8 and Na v 1.9, are exclusively expressed in primary sensory neurons and are suggested to play a role in different pain conditions, including chronic inflammatory and neuropathic pain states. Since no selective pharmacological tools are available, we investigated the involvement of Na v 1.8 and Na v 1.9 in pain transmission by the phenotypic characterization of Na v 1.8 and Na v 1.9 knockout mice and their wild-type littermates in models of acute nociception, peripheral inflammation and neuropathic pain. The present study provides evidence for a modulatory role of Na v 1.9, and to a lesser extent Na v 1.8 in the development of cold, but not mechanical allodynia in neuropathic pain conditions. Moreover, our results also indicate that Na v 1.9 signaling might be involved in visceral pain. In contrast, the presumed critical role of these two sodium channel subtypes to inflammatory pain hypersensitivity seem, according to our results, to be limited and temporarily.
Journal of Cancer Pain Symptom Palliation, 2005
ABSTRACT Animal models were introduced to study bone cancer pain and to develop more effective an... more ABSTRACT Animal models were introduced to study bone cancer pain and to develop more effective and safer analgesics. Three mice models were compared after inducing local tumors by injecting osteolytic fibrosarcoma NCTC2472 cells into the bone, using different injection procedures. Pain behavior was evaluated between days 11-21 after cell injection. Bone lesions were visualized at day 21 using μCT-scanning and histology. All tumor-bearing animals showed pain-related behavior, including spontaneous lifting and, during forced ambulation, decreased limb-use. Lifting on the cold-plate was observed (cold-allodynia) when cells were injected in and around the calcaneus. In all 3 models extensive bone breakdown and invasion of the tumor into the periosteum was observed.
Progress in Neuro Psychopharmacology and Biological Psychiatry, Jul 1, 2011
Recently developed mouse models have implicated the vesicular glutamate transporter 2 (VGLUT2) in... more Recently developed mouse models have implicated the vesicular glutamate transporter 2 (VGLUT2) in psychostimulant-induced hyperactivity, a behavioral assay that is often applied to evaluate mouse behavior related to positive schizophrenia (SCZ) symptomatology. In present research, we wanted to evaluate further the role of subtle VGLUT2 impairment as a factor underlying SCZ symptomatology. To this end, we evaluated Vglut2 haploinsufficient (Vglut2 +/− ) mice and their wildtype littermates in a test battery assessing behaviors related to positive, negative and cognitive SCZ symptom domains. We found in Vglut2 +/− mice an increased locomotor response to amphetamine and an increased sensitivity to the startle-disrupting effects of MK-801, but no impairment in sensorimotor gating. Further on, minor alterations in tests assessing cognitive and negative symptom-related behavior were observed. Possible neurobiological mechanisms of these observations are discussed.
Pharmacology Biochemistry and Behavior, Mar 31, 2007
The intramedulary injection of osteosarcoma cells in the mouse femur has served as a laboratory m... more The intramedulary injection of osteosarcoma cells in the mouse femur has served as a laboratory model to study bone cancer pain. However, the efficacy of different classes of analgesics has not fully been analyzed in this model. Therefore, the acute antinociceptive properties of different classes of drugs were evaluated on post-inoculation day 15 when the degrees of spontaneous pain and mechanical hypersensitivity in the ipsilateral inoculated hind paw reached almost their maximal effects. At high doses, the opioids fentanyl, morphine, and tramadol had full efficacies for all pain parameters tested. Antagonism experiments with naloxone (10 mg/kg s.c.) or its peripheral analogue methylnaltrexone (10 mg/kg s.c.), suggest that the analgesic effects of fentanyl were predominantly mediated by centrally located mu-opiate receptors. Acetaminophen, the non-steroidal anti-inflammatory drug indomethacin, and the COX-2-inhibitor celecoxib did not significantly improve pain behavior. The tricyclic antidepressants amitriptyline and desipramine significantly reduced spontaneous pain behavior but this only at sedative doses; the serotonin reuptake inhibitor fluoxetine had limited efficacy. Also with the anticonvulsants lamotrigine, topiramate, and gabapentin limited or no efficacies were found. In conclusion, the present study provided integrated information about the tumor-induced bone pain in mice, and clarified acute efficacies of different categories of analgesics for the spontaneous lifting, limb-use impairment, and mechanical hypersensitivity. Moreover, the finding that bone cancer-pain behaviors are attenuated by various established compounds further supports the validity of the murine bone cancer model for the study of bone cancer pain and its use for the identification of novel treatments.
BMC research notes, 2016
In this study we explored the possibility of automating the PGP9.5 immunofluorescence staining as... more In this study we explored the possibility of automating the PGP9.5 immunofluorescence staining assay for the diagnosis of small fiber neuropathy using skin punch biopsies. The laboratory developed test (LDT) was subjected to a validation strategy as required by good laboratory practice guidelines and compared to the well-established gold standard method approved by the European Federation of Neurological Societies (EFNS). To facilitate automation, the use of thinner sections. (16 µm) was evaluated. Biopsies from previously published studies were used. The aim was to evaluate the diagnostic performance of the LDT compared to the gold standard. We focused on technical aspects to reach high-quality standardization of the PGP9.5 assay and finally evaluate its potential for use in large scale batch testing. We first studied linear nerve fiber densities in skin of healthy volunteers to establish reference ranges, and compared our LDT using the modifications to the EFNS counting rule to th...
Pharmacology Biochemistry and Behavior, 2002
Animal and clinical studies have reported potentiation of opioid antinociception by NMDA receptor... more Animal and clinical studies have reported potentiation of opioid antinociception by NMDA receptor antagonists such as ketamine and dextromethorphan. The aim of this study was to compare these clinically available NMDA antagonists in combination with classical morphine, mu-selective fentanyl-like opioids, the delta-opioid agonist SNC80 and the kappa-opioid agonist U50,488H. Using a mouse hot-plate test, dose-response relationships were first determined for all compounds individually and then for opioids co-administered with fixed doses of ketamine or dextromethorphan. All compounds were administered intraperitoneally ED(50) values were calculated from the proportion of animals failing to exhibit any response within a fixed cut-off criterion of 30 s. To varying degrees, all compounds produced increases in response latencies over time. Dextromethorphan produced lower ED(50) values for morphine, fentanyl and sufentanil but exerted no effect on the potency of SNC80 or U50,488H. Similarly, ketamine potentiated the antinociceptive potency of morphine, fentanyl and sufentanil but not SNC80 or U50,488H. In summary, these results support the use of mu-opioid agonists in combination with NMDA antagonists, but suggest that there may be no advantage in combining dextromethorphan or ketamine with delta- or kappa-opioids in the management of acute pain.
Pharmacol Biochem Behav, 2004
μ-, κ- and δ-opioid receptor agonists are reported to attenuate the acetic-acid-induced abdominal... more μ-, κ- and δ-opioid receptor agonists are reported to attenuate the acetic-acid-induced abdominal constriction response in mice. NK-1, -2 and -3 receptor antagonists also display activity in several visceral pain models. As the gerbil NK-1 receptor is comparable to the human receptor, we evaluated the efficacy of NK-1, -2 and -3 receptor antagonists and opioids (both alone and in combination) in the writhing test in this species. The effects of a selective L-type calcium (Ca2+) channel antagonist on the writhing response were also assessed to determine the contribution of Ca2+ channel antagonism to the antinociceptive effects of the NK-1 antagonists. Gerbils received subcutaneous injections of either the μ-opioids morphine or fentanyl, the κ-opioid U50,488-H, the δ-opioid SNC80, NK-1 antagonists R116301, CP-96,345 or GR203040, the NK-2 antagonist SR-48968, the NK-3 antagonist SR-142801 or the Ca2+ channel antagonist nimodipine. Writhing was evoked 1 h after treatment by intraperitoneal injection of 0.2 ml 1% acetic acid solution and the frequency was recorded. Morphine, fentanyl and U50,488-H attenuated the writhing response dose dependently with complete inhibition occurring at the highest doses. SNC80 did not significantly attenuate the writhing response even at a dose of 40 mg/kg. The tachykinin NK-1 antagonists CP-96,345 and GR203040, the NK-2 antagonist SR-48968 and the NK-3 antagonist SR-142801 reduced the writhing frequency although without complete inhibition. The NK-1 antagonist R116301 displayed limited activity at doses up to 40 mg/kg. Nimodipine did not exhibit any antinociceptive efficacy in this assay. Adding the NK-1, -2 or -3 antagonists to the opioids did not improve the efficacy of the opioids. Selective NK antagonists may therefore be effective in a visceral nociception assay in gerbils but do not modulate opioid action.
Behavioural Pharmacology, 1992
Rats given a subchronic cocaine treatment for 10 days display an inhibition of exploratory behavi... more Rats given a subchronic cocaine treatment for 10 days display an inhibition of exploratory behaviour 24h after the last cocaine treatment in the open field test. As compared to the vehicle controls, the exploratory inhibition could be measured in terms of a longer latency to enter the open area, a reduction in the time spent in the open field and a decrease in the number of transits from the small dark compartment into the open area. The serotonin (5-HT(2/1C)) antagonist ritanserin, given subcutaneously 1h prior to testing, overcame this behavioural inhibition. At doses between 0.04mg/kg and 10.0mg/kg ritanserin, a complete normalization of exploratory activity was obtained. In chronic vehicle treated rats, ritanserin did not increase exploration. Therefore the effects of ritanserin cannot be attributed to a general activation. The results are discussed with regard to withdrawal anxiety and a possible therapeutic role of ritanserin in drug addicts.
Pharmacology Biochemistry and Behavior, Aug 1, 2007
The primary aim of the study was to describe and correlate pain behavior and changes in bone morp... more The primary aim of the study was to describe and correlate pain behavior and changes in bone morphology in animal models of arthritis both in rats and guinea pigs. Either complete Freund's adjuvant (CFA) or mono-iodoacetate (MIA) solution was injected into the left knee joint to obtain a model for rheumatoid arthritis and osteoarthritis, respectively. Subsequently, animals were behaviorally tested during a period of 12 days after CFA injection and at least 19 days after MIA injection. During these observation periods increasing pain behavior was observed, characterized by decreased von Frey mechanical thresholds and weight bearing on the affected limb. In Hargreaves' paw flick test slightly increased thermal hypersensitivity was observed in some instances in guinea pigs. In rats there was also decreased limb-use during forced ambulation. To evaluate bone destruction mu-computed tomography scans of the arthritic knee were taken on the last experimental day. Different bone parameters indicative of osteolysis and decreased trabecular connectivity were significantly correlated with the observed pain behavior. Detailed description of morphological changes in arthritic joints better characterizes the different animal models and might add to the knowledge on the working mechanisms of analgesic compounds that have an influence on bone structures in arthritis.
Drug Development Research, 1992
Meert, T.F., and P.A.J. Janssen: Ritanserin, a new therapeutic approach for drug abuse.
Bioorg Medicinal Chem Letter, 2006
A novel series of 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives has been prepared and thei... more A novel series of 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives has been prepared and their synthesis described herein. In vitro affinities for δ-, μ-, and κ-opioid receptors, as well as the functional activity in the [35S]GTPγS assay are reported. The most potent and selective δ-opioid agonist 18a exhibited a Ki of 18 nM, and was >258-fold and 28-fold selective over μ- and κ-receptors, respectively; the compound is a full agonist with an EC50 value of 14 nM.A new chemical class of selective δ-opioid agonists based on the 4-phenyl-4-[1H-imidazol-2-yl]-piperidine scaffold is reported. A highly selective δ agonist (18a, EC50 = 14 nM) was identified.
Behavioural Brain Research, Mar 17, 2010
Two voltage gated sodium channels, Na v 1.8 and Na v 1.9, are exclusively expressed in primary se... more Two voltage gated sodium channels, Na v 1.8 and Na v 1.9, are exclusively expressed in primary sensory neurons and are suggested to play a role in different pain conditions, including chronic inflammatory and neuropathic pain states. Since no selective pharmacological tools are available, we investigated the involvement of Na v 1.8 and Na v 1.9 in pain transmission by the phenotypic characterization of Na v 1.8 and Na v 1.9 knockout mice and their wild-type littermates in models of acute nociception, peripheral inflammation and neuropathic pain. The present study provides evidence for a modulatory role of Na v 1.9, and to a lesser extent Na v 1.8 in the development of cold, but not mechanical allodynia in neuropathic pain conditions. Moreover, our results also indicate that Na v 1.9 signaling might be involved in visceral pain. In contrast, the presumed critical role of these two sodium channel subtypes to inflammatory pain hypersensitivity seem, according to our results, to be limited and temporarily.
Journal of Cancer Pain Symptom Palliation, 2005
ABSTRACT Animal models were introduced to study bone cancer pain and to develop more effective an... more ABSTRACT Animal models were introduced to study bone cancer pain and to develop more effective and safer analgesics. Three mice models were compared after inducing local tumors by injecting osteolytic fibrosarcoma NCTC2472 cells into the bone, using different injection procedures. Pain behavior was evaluated between days 11-21 after cell injection. Bone lesions were visualized at day 21 using μCT-scanning and histology. All tumor-bearing animals showed pain-related behavior, including spontaneous lifting and, during forced ambulation, decreased limb-use. Lifting on the cold-plate was observed (cold-allodynia) when cells were injected in and around the calcaneus. In all 3 models extensive bone breakdown and invasion of the tumor into the periosteum was observed.
Progress in Neuro Psychopharmacology and Biological Psychiatry, Jul 1, 2011
Recently developed mouse models have implicated the vesicular glutamate transporter 2 (VGLUT2) in... more Recently developed mouse models have implicated the vesicular glutamate transporter 2 (VGLUT2) in psychostimulant-induced hyperactivity, a behavioral assay that is often applied to evaluate mouse behavior related to positive schizophrenia (SCZ) symptomatology. In present research, we wanted to evaluate further the role of subtle VGLUT2 impairment as a factor underlying SCZ symptomatology. To this end, we evaluated Vglut2 haploinsufficient (Vglut2 +/− ) mice and their wildtype littermates in a test battery assessing behaviors related to positive, negative and cognitive SCZ symptom domains. We found in Vglut2 +/− mice an increased locomotor response to amphetamine and an increased sensitivity to the startle-disrupting effects of MK-801, but no impairment in sensorimotor gating. Further on, minor alterations in tests assessing cognitive and negative symptom-related behavior were observed. Possible neurobiological mechanisms of these observations are discussed.
Pharmacology Biochemistry and Behavior, Mar 31, 2007
The intramedulary injection of osteosarcoma cells in the mouse femur has served as a laboratory m... more The intramedulary injection of osteosarcoma cells in the mouse femur has served as a laboratory model to study bone cancer pain. However, the efficacy of different classes of analgesics has not fully been analyzed in this model. Therefore, the acute antinociceptive properties of different classes of drugs were evaluated on post-inoculation day 15 when the degrees of spontaneous pain and mechanical hypersensitivity in the ipsilateral inoculated hind paw reached almost their maximal effects. At high doses, the opioids fentanyl, morphine, and tramadol had full efficacies for all pain parameters tested. Antagonism experiments with naloxone (10 mg/kg s.c.) or its peripheral analogue methylnaltrexone (10 mg/kg s.c.), suggest that the analgesic effects of fentanyl were predominantly mediated by centrally located mu-opiate receptors. Acetaminophen, the non-steroidal anti-inflammatory drug indomethacin, and the COX-2-inhibitor celecoxib did not significantly improve pain behavior. The tricyclic antidepressants amitriptyline and desipramine significantly reduced spontaneous pain behavior but this only at sedative doses; the serotonin reuptake inhibitor fluoxetine had limited efficacy. Also with the anticonvulsants lamotrigine, topiramate, and gabapentin limited or no efficacies were found. In conclusion, the present study provided integrated information about the tumor-induced bone pain in mice, and clarified acute efficacies of different categories of analgesics for the spontaneous lifting, limb-use impairment, and mechanical hypersensitivity. Moreover, the finding that bone cancer-pain behaviors are attenuated by various established compounds further supports the validity of the murine bone cancer model for the study of bone cancer pain and its use for the identification of novel treatments.
BMC research notes, 2016
In this study we explored the possibility of automating the PGP9.5 immunofluorescence staining as... more In this study we explored the possibility of automating the PGP9.5 immunofluorescence staining assay for the diagnosis of small fiber neuropathy using skin punch biopsies. The laboratory developed test (LDT) was subjected to a validation strategy as required by good laboratory practice guidelines and compared to the well-established gold standard method approved by the European Federation of Neurological Societies (EFNS). To facilitate automation, the use of thinner sections. (16 µm) was evaluated. Biopsies from previously published studies were used. The aim was to evaluate the diagnostic performance of the LDT compared to the gold standard. We focused on technical aspects to reach high-quality standardization of the PGP9.5 assay and finally evaluate its potential for use in large scale batch testing. We first studied linear nerve fiber densities in skin of healthy volunteers to establish reference ranges, and compared our LDT using the modifications to the EFNS counting rule to th...
Pharmacology Biochemistry and Behavior, 2002
Animal and clinical studies have reported potentiation of opioid antinociception by NMDA receptor... more Animal and clinical studies have reported potentiation of opioid antinociception by NMDA receptor antagonists such as ketamine and dextromethorphan. The aim of this study was to compare these clinically available NMDA antagonists in combination with classical morphine, mu-selective fentanyl-like opioids, the delta-opioid agonist SNC80 and the kappa-opioid agonist U50,488H. Using a mouse hot-plate test, dose-response relationships were first determined for all compounds individually and then for opioids co-administered with fixed doses of ketamine or dextromethorphan. All compounds were administered intraperitoneally ED(50) values were calculated from the proportion of animals failing to exhibit any response within a fixed cut-off criterion of 30 s. To varying degrees, all compounds produced increases in response latencies over time. Dextromethorphan produced lower ED(50) values for morphine, fentanyl and sufentanil but exerted no effect on the potency of SNC80 or U50,488H. Similarly, ketamine potentiated the antinociceptive potency of morphine, fentanyl and sufentanil but not SNC80 or U50,488H. In summary, these results support the use of mu-opioid agonists in combination with NMDA antagonists, but suggest that there may be no advantage in combining dextromethorphan or ketamine with delta- or kappa-opioids in the management of acute pain.
Pharmacol Biochem Behav, 2004
μ-, κ- and δ-opioid receptor agonists are reported to attenuate the acetic-acid-induced abdominal... more μ-, κ- and δ-opioid receptor agonists are reported to attenuate the acetic-acid-induced abdominal constriction response in mice. NK-1, -2 and -3 receptor antagonists also display activity in several visceral pain models. As the gerbil NK-1 receptor is comparable to the human receptor, we evaluated the efficacy of NK-1, -2 and -3 receptor antagonists and opioids (both alone and in combination) in the writhing test in this species. The effects of a selective L-type calcium (Ca2+) channel antagonist on the writhing response were also assessed to determine the contribution of Ca2+ channel antagonism to the antinociceptive effects of the NK-1 antagonists. Gerbils received subcutaneous injections of either the μ-opioids morphine or fentanyl, the κ-opioid U50,488-H, the δ-opioid SNC80, NK-1 antagonists R116301, CP-96,345 or GR203040, the NK-2 antagonist SR-48968, the NK-3 antagonist SR-142801 or the Ca2+ channel antagonist nimodipine. Writhing was evoked 1 h after treatment by intraperitoneal injection of 0.2 ml 1% acetic acid solution and the frequency was recorded. Morphine, fentanyl and U50,488-H attenuated the writhing response dose dependently with complete inhibition occurring at the highest doses. SNC80 did not significantly attenuate the writhing response even at a dose of 40 mg/kg. The tachykinin NK-1 antagonists CP-96,345 and GR203040, the NK-2 antagonist SR-48968 and the NK-3 antagonist SR-142801 reduced the writhing frequency although without complete inhibition. The NK-1 antagonist R116301 displayed limited activity at doses up to 40 mg/kg. Nimodipine did not exhibit any antinociceptive efficacy in this assay. Adding the NK-1, -2 or -3 antagonists to the opioids did not improve the efficacy of the opioids. Selective NK antagonists may therefore be effective in a visceral nociception assay in gerbils but do not modulate opioid action.