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... 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.
Research Interests:
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... 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.
Research Interests: Pharmacology, Computed Tomography, Animal Behavior, Pain, Behavior, and 17 moreEvaluation, Rheumatoid Arthritis, Osteoarthritis, Animals, Male, Animal Model, Ct Scan, Rats, Rat, Guinea Pig, Joints, Postural Balance, X ray Computed Tomography, Weight Bearing, Knee Joint, Bone and Bones, and Pain Threshold
Research Interests:
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... 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.
Research Interests:
Research Interests:
Research Interests:
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... 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.
Research Interests:
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.... 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.
Research Interests: Pain, Cancer, Evaluation, Treatment, Models, and 5 moreMice, Animals, Osteosarcoma, Male, and Hypersensitivity
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... 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...
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... 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.
Research Interests:
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... 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.
Research Interests:
Research Interests:
The present experiments were designed to investigate the role of housing and handling conditions during testing, as well as data analysis, on the outcome of antinociceptive testing of alpha 2-adrenoceptor agonists, fentanyl, and a high... more
The present experiments were designed to investigate the role of housing and handling conditions during testing, as well as data analysis, on the outcome of antinociceptive testing of alpha 2-adrenoceptor agonists, fentanyl, and a high dose of chlordiazepoxide in the tail withdrawal reaction test (TWR test) in rats. Dose-response curve data were obtained with fentanyl, clonidine, xylazine, dexmedetomidine, and 40.00 mg/kg chlordiazepoxide and were compared under normal TWR test conditions and during immobilization or immobilization with continuous painful stimulation. Data were analyzed in terms of all-or-none criteria as well as percentage maximum possible effect (%MPE) analysis over the total measurement period or at any specific time point during testing. The results indicate that stress, induced by immobilization and immobilization with long-term-applied paw pressure, unmasked possible antinociceptive properties of the various alpha 2-adrenoceptor agonists and potentiated the effects of fentanyl. Stress also unmasked the positive effects of benzodiazepines. The manner of data analysis was shown to significantly affect the outcome measured in stress and nonstress conditions. The MPE analysis, particularly at one time point, appeared much more sensitive than the all-or-none criteria. The data indicate that the housing and handling conditions of animals during testing, together with data analysis, may affect the outcome of different classes of compounds in the TWR test, and this knowledge may help control for false positive results.
Research Interests:
Research Interests:
Research Interests: Animal Behavior, Diet, Alcoholism, Animals, Male, and 7 moreEthanol, Tremor, Rats, Rat, Wistar Rats, Exploratory Behavior, and Harmine
NMRInu/nu mice are frequently used in cancer research, but their use in behavioural pain tests is unexplored. As behaviour of NMRI mice in pain tests is well-documented, a hot-plate test was performed comparing acute thermal nociception... more
NMRInu/nu mice are frequently used in cancer research, but their use in behavioural pain tests is unexplored. As behaviour of NMRI mice in pain tests is well-documented, a hot-plate test was performed comparing acute thermal nociception in NMRInu/nu and NMRI mice - untreated and morphine-treated - to estimate the usefulness of NMRInu/nu mice for further research on cancer pain. In both strains, morphine dose-dependently increased response latencies, number of animals reaching cut-off times and AUC values. Yet in NMRInu/nu mice, as compared to NMRI mice, all curves were shifted to the right. In order to be comparable, cut-off times must express a similar degree of baseline response augmentations. NMRInu/nu mice had substantially lower pre-drug latencies, indicating a lowered threshold for painful thermal stimuli, therefore effects of morphine in NMRInu/nu mice were also analysed using a lower cut-off time. Doing so, morphine resulted in similar effects in both strains. The effects were independent of hot-plate temperature, because similar results were obtained using temperatures of 50 and 55 degrees. The different morphine sensitivity of NMRInu/nu compared to NMRI mice primarily seems to depend upon differences in thermal threshold, probably induced by the different genotype of both strains. To determine whether cancer alters pain threshold or morphine analgesia, LoVo tumour-bearing NMRInu/nu mice were also tested. The tumour presence had no influence on withdrawal latencies or morphine efficacy. In general it can be concluded that NMRInu/nu mice with or without tumour can be used for nociceptive testing if baseline sensitivity is properly defined.
Research Interests:
Phosphodiesterases (PDEs) form a family of enzymes involved in the hydrolysis of cyclic adenosine and guanosine monophosphate (cAMP and cGMP). PDE10A is a member of this family that is almost exclusively expressed in the striatum.... more
Phosphodiesterases (PDEs) form a family of enzymes involved in the hydrolysis of cyclic adenosine and guanosine monophosphate (cAMP and cGMP). PDE10A is a member of this family that is almost exclusively expressed in the striatum. Increasing cAMP/cGMP levels via inhibition of PDE10A is under consideration as a novel therapeutic avenue in the discovery of antipsychotics. Papaverine has been used as a pharmacological tool to establish the possible clinical use of PDE10A inhibitors as antipsychotics. Papaverine is known to increase cAMP levels in striatum and to decrease blood pressure, body temperature and locomotor activity after systemic administration. In this study, the effects of papaverine are compared to those of a more specific PDE10A inhibitor MP10. Papaverine raised striatal cAMP levels with hypothermia, hypoactivity and decreased cardiovascular responses. The more selective MP10 had significantly less effects on body temperature and cardiovascular functions, but reduced locomotor activity to a similar extend as papaverine.
Research Interests:
Although exogenous opioids alter the responses of animals to tissue-damaging stimuli and therefore are the cornerstone in the treatment of acute antinociception, they have profound side effects on ventilation. To diminish ventilatory... more
Although exogenous opioids alter the responses of animals to tissue-damaging stimuli and therefore are the cornerstone in the treatment of acute antinociception, they have profound side effects on ventilation. To diminish ventilatory effects, combination therapies have been advocated. Recent studies reported the effectiveness of the addition of N-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine to morphine in the treatment of acute pain. However, NMDA receptors, together with non-NMDA receptors are known to be involved in the neurotransmission of inspiratory drive to phrenic motoneurons. Co-administration of NMDA and non-NMDA receptor antagonists has been shown to be deleterious to respiratory function. The present study investigated the hypothesis that the association of opioids and NMDA receptor antagonists may add to the impairment of respiratory parameters. In male Wistar rats, combinations of opioids (fentanyl or morphine) at antinociceptive doses and NMDA receptor antagonists (ketamine, 40 mg/kg, or dextromethorphan, 10 mg/kg) at subanesthetic doses were administered intraperitoneally. Antinociception was tested with the tail-withdrawal reaction (TWR) test, while the effect on respiratory parameters was investigated with blood-gas analysis. We found that, in rats, co-administration of NMDA receptor antagonists and opioids may result in an increased respiratory depression as compared to the opioids alone. The effect of the NMDA receptor antagonists on opioid-induced antinociception was limited.
Research Interests:
Research Interests:
Research Interests:
Rats given a 10% (v/v) alcohol liquid diet over two weeks reached high blood alcohol levels of around 200mg/dl. Discontinuation of the alcohol intake resulted within 6h in several withdrawal reactions including a tremorogenic activity and... more
Rats given a 10% (v/v) alcohol liquid diet over two weeks reached high blood alcohol levels of around 200mg/dl. Discontinuation of the alcohol intake resulted within 6h in several withdrawal reactions including a tremorogenic activity and a reduction in exploratory behaviour in novel environments. The tremorogenic activity of the alcohol withdrawal could be quantified, using a piezo-film technique, in terms of a supersensitivity to both an inactive and a moderately active dose of the tremorogenic compound harmine. As compared to controls, the rats in alcohol withdrawal revealed more frequent tremor after both 5 and 10mg/kg harmine. The supersensitivity to harmine-induced tremor started within 6h after alcohol withdrawal and remained present with 10mg/kg harmine for up to 48h. The supersensitivity was independent of the length of the tremor bursts used to quantify harmine-induced tremor. Alcohol withdrawal also resulted in an inhibition of exploratory behaviour in a neutral two-chamber box. Both in terms of the number of transits into the open field as well as the time spent in the open area, rats in alcohol withdrawal were significantly less active than control animals. The reduced exploration started within 6h after withdrawal and remained present for up to 24h after the last alcohol intake. These results indicate that both alcohol withdrawal-induced sensitivity to tremorogenic agents and inhibition of exploratory behaviour can be quantified over time, allowing the pharmacological mechanisms involved to be studied.
Research Interests:
Research Interests:
ABSTRACT
Research Interests:
The present study was designed to investigate the possible role of some alpha 2-agonists in the phenomenon of tolerance to opioid-induced antinociception. To do so, the alpha 2-agonists were tested alone and in combination with opioids in... more
The present study was designed to investigate the possible role of some alpha 2-agonists in the phenomenon of tolerance to opioid-induced antinociception. To do so, the alpha 2-agonists were tested alone and in combination with opioids in naive and repeatedly fentanyl-treated rats in the tail withdrawal reaction (TWR) test. Under the treatment schedule used, rats became tolerant to fentanyl and cross-tolerance was observed with other opioids. The alpha 2-agonists alone were inactive in opioid naive and repeatedly fentanyl-treated rats. The potentiating interaction between the alpha 2-agonists and fentanyl in naive animals diminished considerably after the repeated fentanyl treatment. Adding an alpha 2-agonist to high doses of fentanyl during repeated treatment resulted in a complete tolerance to both compounds. Using lower, but equipotent antinociceptive drug combinations of alpha 2-agonists and opioids, resulted in less tolerance. Alpha 2-agonists are thus unable to directly overcome tolerance to the antinociceptive activity of fentanyl in tolerant animals. Nevertheless, by lowering the dose of the opioid for an equipotent antinociceptive activity, alpha 2-agonists are able to delay the onset of tolerance, probably based on the concept of opioid receptor sparing.
Research Interests:
Research Interests:
Several binding studies in rodent brain homogenates have revealed two distinct micro-opiate binding sites based on differences in binding affinity of several opiate peptides and opiate alkaloids. Naloxonazine (NLZ), which preferentially... more
Several binding studies in rodent brain homogenates have revealed two distinct micro-opiate binding sites based on differences in binding affinity of several opiate peptides and opiate alkaloids. Naloxonazine (NLZ), which preferentially binds to the high affinity micro(1) sites, is often used to discriminate between pharmacological effects mediated by micro(1) and micro(2) binding sites. The present series of experiments were undertaken to compare the opioid antagonistic properties of naloxonazine and naloxone (NLX) (a non-selective micro(1)-antagonist) on intravenous (i.v.) and intrathecal (i.t.) sufentanil (SUF)-induced antinociception and respiratory depression. The opioid antagonists were given either intravenously at 5 min after SUF, or subcutaneously (s.c.) 24 h prior to the opioid. Intravenous NLX and NLZ reduced the i.v. and i. t. SUF-induced antinociception, hypercapnia and hypoxia when given directly after the opioid. There were no major differences in activity between both antagonists. Pretreatment with 30 mg/kg NLX did not reverse the i.v. or i.t. SUF-induced antinociception and respiratory depression. Subcutaneous pretreatment with doses up to 30 mg/kg NLX only partially antagonized the i.v. SUF-induced antinociception, while a complete reversal was present of the opioid-induced hypercapnia and hypoxia. With regard to i.t. SUF, doses up to 30 mg/kg NLZ were unable to reduce the antinociception. The respiratory depression was partially affected; with 30 mg/kg NLZ, the i.t. SUF-induced hypercapnia returned to baseline levels, whereas the SUF-induced hypoxia was only minimally affected. These results challenge the classical view of the selectivity of NLZ for the high affinity micro(1) binding sites. They further fail to conform an exclusive role for micro(2) receptor sites in the respiratory depression and spinal analgesia induced by a strong lipophilic opioid such as SUF in rats.
Research Interests:
Animal and clinical studies have reported potentiation of opioid antinociception by co-administration of alpha-2 adrenoceptor agonists such as clonidine and NMDA receptor antagonists such as ketamine and dextromethorphan. The aim of this... more
Animal and clinical studies have reported potentiation of opioid antinociception by co-administration of alpha-2 adrenoceptor agonists such as clonidine and NMDA receptor antagonists such as ketamine and dextromethorphan. The aim of this study was to compare these clinically available compounds in combination with classical morphine, 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 clonidine, ketamine or dextromethorphan. Clonidine was also evaluated in combination with ketamine and dextromethorphan. ED50 values were calculated from the proportion of animals reaching a fixed cut-off criterion of 30 s. To varying degrees, all compounds produced increases in response latencies over time. Dextromethorphan produced lower ED50 values for morphine, fentanyl and sufentanil but exer...
Research Interests:
Research Interests:
Although opioids provide effective analgesia, largely unsubstantiated concerns about opioid-induced tolerance, physical dependence and addiction have limited their appropriate use. As a consequence, many patients receive inadequate... more
Although opioids provide effective analgesia, largely unsubstantiated concerns about opioid-induced tolerance, physical dependence and addiction have limited their appropriate use. As a consequence, many patients receive inadequate treatment for both malignant and non-malignant pain. However, it has been shown that analgesic tolerance develops less frequently during chronic opioid administration in a clinical context than in animal experiments, and that instituting an appropriate dosing regimen can minimise withdrawal symptoms. Early studies had suggested that addiction might result from chronic opioid therapy, though more recent data indicate a low risk in patients with no history of drug abuse. New treatment regimens may also reduce the risk of tolerance, physical dependence and addiction. Long-acting preparations, such as transdermal fentanyl and possibly some forms of other slow release opioids, which maintain constant opioid concentrations in the plasma, minimise the occurrence...
Research Interests:
Clinical observations indicate that activation of the TNF-α system may contribute to the development of inflammation-associated depression. Here, we tested the hypothesis that systemic upregulation of TNF-α induces neuroinflammation and... more
Clinical observations indicate that activation of the TNF-α system may contribute to the development of inflammation-associated depression. Here, we tested the hypothesis that systemic upregulation of TNF-α induces neuroinflammation and behavioral changes relevant to depression. We report that a single intraperitoneal injection of TNF-α in mice increased serum and brain levels of the proinflammatory mediators TNF-α, IL-6, and MCP-1, in a dose- and time-dependent manner, but not IL-1β. Protein levels of the anti-inflammatory cytokine IL-10 increased in serum but not in the brain. The transient release of immune molecules was followed by glial cell activation as indicated by increased astrocyte activation in bioluminescent Gfap-luc mice and elevated immunoreactivity against the microglial marker Iba1 in the dentate gyrus of TNF-α-challenged mice. Additionally, TNF-α-injected mice were evaluated in a panel of behavioral tests commonly used to study sickness and depressive-like behavior in rodents. Our behavioral data imply that systemic administration of TNF-α induces a strong sickness response characterized by reduced locomotor activity, decreased fluid intake, and body weight loss. Depressive-like behavior could not be separated from sickness at any of the time points studied. Together, these results demonstrate that peripheral TNF-α affects the central nervous system at a neuroimmune and behavioral level.
Research Interests:
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... 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.
ABSTRACT Described here are the effects over time of a tibial and sural nerve transection model, two branches of sciatic nerve in rats, as a model of neuropathic pain syndromes in man. In two series of experiments conducted over a period... more
ABSTRACT Described here are the effects over time of a tibial and sural nerve transection model, two branches of sciatic nerve in rats, as a model of neuropathic pain syndromes in man. In two series of experiments conducted over a period of 56 days, it was demonstrated that transection of 2 of the 3 branches of the sciaticus resulted in a reproducible series of sensory deficits including cold, chemical, and mechanical allodynia and mechanical hyperalgesia. Most of the behavioral measurements started at day 3 after surgery and reached maximum effect within 1–2 weeks. The effects remained present over the 56 days measurement period. Nothing was seen on the thermal allodynia or on spontaneous pain behavioral tests. These results indicate that cutting of tibial and sural nerves results in a reproducible model of neuropathic pain syndromes with clear measurements of allodynia and hyperalgesia, and thus can be used for research and drug testing.
Phosphodiesterases (PDEs) form a family of enzymes involved in the hydrolysis of cyclic adenosine and guanosine monophosphate (cAMP and cGMP). PDE10A is a member of this family that is almost exclusively expressed in the striatum.... more
Phosphodiesterases (PDEs) form a family of enzymes involved in the hydrolysis of cyclic adenosine and guanosine monophosphate (cAMP and cGMP). PDE10A is a member of this family that is almost exclusively expressed in the striatum. Increasing cAMP/cGMP levels via inhibition of PDE10A is under consideration as a novel therapeutic avenue in the discovery of antipsychotics. Papaverine has been used as a pharmacological tool to establish the possible clinical use of PDE10A inhibitors as antipsychotics. Papaverine is known to increase cAMP levels in striatum and to decrease blood pressure, body temperature and locomotor activity after systemic administration. In this study, the effects of papaverine are compared to those of a more specific PDE10A inhibitor MP10. Papaverine raised striatal cAMP levels with hypothermia, hypoactivity and decreased cardiovascular responses. The more selective MP10 had significantly less effects on body temperature and cardiovascular functions, but reduced loc...