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314 IN VIVO CHARACTERIZATION OF SELECTIVE TRPV1 ANTAGONIST BCTC IN DIFFERENT ANIMAL MODELS OF ACUTE AND CHRONIC PAIN
S84
European Journal of Pain 2006, Vol 10 (suppl S1)
in thalamus, basal ganglia, insula, secondary somatosensory cortex (SII) and anterior cingulate cortex (ACC), and in the right cerebellum. The group map from the rotations of the non-painful shoulder demonstrated activity only in contralateral SII and insula. Conclusions: We have shown that movement induced allodynia is measurable using fMRI. Movement induced allodynia in the diseased shoulder activated the pain matrix while the identical range of movement in the normal shoulder did not. Patients are currently being assessed post surgically to determine whether objective fMRI related brain activity changes concur with subjective rating changes. 313 CHANGES IN BRAIN ACTIVATION RELATED TO PAIN RELIEF IN RHEUMATOID ARTHRITIS PATIENTS FOLLOWING ANTI-TNF TREATMENT K. Wartolowska1,2 ° , P. Schweinhardt1,2 , P. Wordsworth3 , B.A. Chizh4 , C. Bountra4 , I. Tracey1,2 . 1 Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, 2 Centre for Functional Magnetic Resonance Imaging of the Brain, Department of Clinical Neurology, University of Oxford, Oxford, 3 Nuffield Department of Orthopaedic Surgery, Nuffield Orthopaedic Centre, Oxford, 4 GlaxoSmithKline Research and Development, GlaxoSmithKline, Harlow, UK Background and Aims: Functional magnetic resonance imaging (fMRI) offers comprehensive information on brain function. The objective fMRI data can be correlated with behavioural and clinical measures to help dissect a subjective pain experience into its components. In this study, we compared changes of experimental and clinical pain processing in rheumatoid arthritis (RA) before and after treatment with etanercept or infliximab; agents that block the action of proinflammatory cytokine, tumor necrosis factor (anti-TNF). Methods: We recruited 10 patients with active rheumatoid arthritis (RA) due to begin the anti-TNF treatment and 10 age and sex matched healthy volunteers. We used fMRI to investigate changes in brain activation patterns in response to clinically-relevant stimuli (joint squeeze and experimental heat pain stimulation) pre- and post-treatment. We collected also clinical and psychophysical information from each patient. Results: We observed robust activation in response to both clinical and experimental pain in all major pain processing areas. Preliminary analysis suggests that fMRI is able to detect differences in experimental pain processing between patients and healthy subjects, as well as differences between clinical and experimental pain in RA patients alone. We found significant (p < 0.05) decreases in pain ratings for both kinds of stimuli, clinical markers of inflammation, disease activity score (DAS 28) and significant changes in fMRI signal in insula cortex post anti-TNF treatment. Conclusions: Our findings suggest that fMRI is a sensitive measure of pain experience and has the potential to become a useful tool in understanding pathophysiology of chronic pain as well as measuring treatment effects. B12 NON-OPIOID ANALGESICS 314 IN VIVO CHARACTERIZATION OF SELECTIVE TRPV1 ANTAGONIST BCTC IN DIFFERENT ANIMAL MODELS OF ACUTE AND CHRONIC PAIN K. Arndt ° , A. Ceci, W. Gaida, H. Doods. Boehringer Ingelheim Pharma GmbH and Co KG, Germany Background and Aims: Vanilloid receptor 1 (TRPV1) is a ligandgated non-selective cation channel and is recognized as a polymodal nociceptor, which integrates multiple pain stimuli, e.g., noxious heat, protons and vanilloids (Tominaga, 1998). N-(4-Tertiarybutylphenyl)-4(3-chlorophyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC) is a recently described selective inhibitor of capsaicin- and acid-mediated currents at rat TRPV1. In rats, BCTC significantly attenuated mechanical hyperalgesia and tactile allodynia in two models of mononeuropathic pain i.e. partial sciatic nerve (PNL; Pomonis, 2003) and chronic constriction injury (CCI; Kanai, 2005). Here we examined the effects of BCTC in
Abstracts, 5th EFIC Congress, Free Presentations acute pain (tail flick and hot plate), neuropathic pain (PNL and streptozocin (STZ)-induced diabetic polyneuropaty) and in two models of inflammation (CFA and formalin paw test). Methods: PNL nerve injury was performed according to the method by Seltzer (Seltzer, 1990). Paw inflammation was induced by injection of CFA or formalin into the left hindpaw. Diabetes was induced in rats with STZ 65 mg/kg i.p. following an overnight fast. Mechanical thresholds (allodynia and hyperalgesia) were assessed. Results: BCTC at doses of 10, 30 and 100 mg/kg shows antinociceptive activity in the PNL model. BCTC was not active in all other pain models employed. Together, our data suggest that TRPV1 blockade is active only in a limited set of pain models. Conclusions: If this limited efficacy also translates into the human situation has to be shown. 315 THE MEDICINAL HERB GINKGO BILOBA REVERSES THERMAL HYPERALGESIA IN A MODEL OF POST-SURGICAL PAIN L. Biddlestone ° , S. Dolan. Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow, UK Recent studies in vitro suggest that Gingko biloba has anti-inflammatory properties but analgesic properties are unknown. The aim of this study is to determine if Ginkgo biloba extract, EGb-761 (gifted from Dr Schwabe Pharmaceuticals) is analgesic in an animal model of post-surgical pain. Adult male Wistar rats (n = 6/group; 250–310 g) were anaesthetised with isoflurane and a longitudal 1 cm incision was made through the skin, fascia and plantaris muscle of the hindpaw. Control animals were subjected to anaesthesia only (n = 7). Hindpaw withdrawal latency (in secs) to thermal stimulation and response threshold (in grams) to mechanical stimulation were measured before surgery and at 2, 4, 6 h, and 1, 2, 3 and 8 days after surgery. The effect of oral administration of Ginkgo biloba extract (30, 100 and 300 mg/g) or drug-vehicle at 3 h post-surgery on response thresholds were assessed. Data are mean maximum decrease (%) from baseline ± SEM. Drug-vehicle treated animals displayed maximum thermal hyperalgesia (56.9±4.0%; p < 0.001) and mechanical allodynia (45.4±4.8%; p < 0.001) 6 h post-surgery. Administration of Ginkgo biloba (30, 100 and 300 mg/kg) blocked thermal hyperalgesia at 6 h (22.6±5.1%, 12.0±5.4% and 6.9±4.7%; respectively; p < 0.001 vs. vehicle). Administration of Ginkgo biloba had no effect on mechanical allodynia. These results demonstrate that Ginkgo biloba has significant analgesic activity in this model, suggesting that it may be a useful therapeutic agent for the treatment of surgical pain.
316 COMPARISON OF CAUDAL EPIDURAL ANESTHESIA WITH LIDOCAINE-DISTILLED WATER AND LIDOCAINE-MGSO4 MIXTURE IN DOGS A. Bigham Sadegh ° , S. Dehghani, Z. Shafiei. Department of Veterinary Surgery, Veterinary Medicine School, Shiraz University, Shiraz, Iran Objective: To directly compare the time to recumbency, onset, duration of analgesia and standing produced by a Lidocaine-MgSO4 combination with that produced by Lidocaine-Distilled water administration in the caudal epidural space of indigenous awake dogs. Animal Five (<1 year old) female indigenous dogs weighting (10.74±0.44 kg). Methods: Epidural anesthesia was produced in all dogs with 2% lidocaine (1 ml/4.5 kg body weight) with 1 ml distilled water and two weeks later repeated by lidocaine (1 ml/4.5 kg) with 1 ml of 10% MgSO4. Time to recumbency, onset, duration of analgesia and cranial spread of analgesia with standing time were recorded. Heart rate, Respiratory rate and body temperature were recorded at 0 minute prior to epidural administrations of each treatments as a base line values and at 5, 10, 15, 30, 60 and 75 minutes after the epidural administrations. Statistical
European Journal of Pain 2006, Vol 10 (suppl S1)
in thalamus, basal ganglia, insula, secondary somatosensory cortex (SII) and anterior cingulate cortex (ACC), and in the right cerebellum. The group map from the rotations of the non-painful shoulder demonstrated activity only in contralateral SII and insula. Conclusions: We have shown that movement induced allodynia is measurable using fMRI. Movement induced allodynia in the diseased shoulder activated the pain matrix while the identical range of movement in the normal shoulder did not. Patients are currently being assessed post surgically to determine whether objective fMRI related brain activity changes concur with subjective rating changes. 313 CHANGES IN BRAIN ACTIVATION RELATED TO PAIN RELIEF IN RHEUMATOID ARTHRITIS PATIENTS FOLLOWING ANTI-TNF TREATMENT K. Wartolowska1,2 ° , P. Schweinhardt1,2 , P. Wordsworth3 , B.A. Chizh4 , C. Bountra4 , I. Tracey1,2 . 1 Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, 2 Centre for Functional Magnetic Resonance Imaging of the Brain, Department of Clinical Neurology, University of Oxford, Oxford, 3 Nuffield Department of Orthopaedic Surgery, Nuffield Orthopaedic Centre, Oxford, 4 GlaxoSmithKline Research and Development, GlaxoSmithKline, Harlow, UK Background and Aims: Functional magnetic resonance imaging (fMRI) offers comprehensive information on brain function. The objective fMRI data can be correlated with behavioural and clinical measures to help dissect a subjective pain experience into its components. In this study, we compared changes of experimental and clinical pain processing in rheumatoid arthritis (RA) before and after treatment with etanercept or infliximab; agents that block the action of proinflammatory cytokine, tumor necrosis factor (anti-TNF). Methods: We recruited 10 patients with active rheumatoid arthritis (RA) due to begin the anti-TNF treatment and 10 age and sex matched healthy volunteers. We used fMRI to investigate changes in brain activation patterns in response to clinically-relevant stimuli (joint squeeze and experimental heat pain stimulation) pre- and post-treatment. We collected also clinical and psychophysical information from each patient. Results: We observed robust activation in response to both clinical and experimental pain in all major pain processing areas. Preliminary analysis suggests that fMRI is able to detect differences in experimental pain processing between patients and healthy subjects, as well as differences between clinical and experimental pain in RA patients alone. We found significant (p < 0.05) decreases in pain ratings for both kinds of stimuli, clinical markers of inflammation, disease activity score (DAS 28) and significant changes in fMRI signal in insula cortex post anti-TNF treatment. Conclusions: Our findings suggest that fMRI is a sensitive measure of pain experience and has the potential to become a useful tool in understanding pathophysiology of chronic pain as well as measuring treatment effects. B12 NON-OPIOID ANALGESICS 314 IN VIVO CHARACTERIZATION OF SELECTIVE TRPV1 ANTAGONIST BCTC IN DIFFERENT ANIMAL MODELS OF ACUTE AND CHRONIC PAIN K. Arndt ° , A. Ceci, W. Gaida, H. Doods. Boehringer Ingelheim Pharma GmbH and Co KG, Germany Background and Aims: Vanilloid receptor 1 (TRPV1) is a ligandgated non-selective cation channel and is recognized as a polymodal nociceptor, which integrates multiple pain stimuli, e.g., noxious heat, protons and vanilloids (Tominaga, 1998). N-(4-Tertiarybutylphenyl)-4(3-chlorophyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC) is a recently described selective inhibitor of capsaicin- and acid-mediated currents at rat TRPV1. In rats, BCTC significantly attenuated mechanical hyperalgesia and tactile allodynia in two models of mononeuropathic pain i.e. partial sciatic nerve (PNL; Pomonis, 2003) and chronic constriction injury (CCI; Kanai, 2005). Here we examined the effects of BCTC in
Abstracts, 5th EFIC Congress, Free Presentations acute pain (tail flick and hot plate), neuropathic pain (PNL and streptozocin (STZ)-induced diabetic polyneuropaty) and in two models of inflammation (CFA and formalin paw test). Methods: PNL nerve injury was performed according to the method by Seltzer (Seltzer, 1990). Paw inflammation was induced by injection of CFA or formalin into the left hindpaw. Diabetes was induced in rats with STZ 65 mg/kg i.p. following an overnight fast. Mechanical thresholds (allodynia and hyperalgesia) were assessed. Results: BCTC at doses of 10, 30 and 100 mg/kg shows antinociceptive activity in the PNL model. BCTC was not active in all other pain models employed. Together, our data suggest that TRPV1 blockade is active only in a limited set of pain models. Conclusions: If this limited efficacy also translates into the human situation has to be shown. 315 THE MEDICINAL HERB GINKGO BILOBA REVERSES THERMAL HYPERALGESIA IN A MODEL OF POST-SURGICAL PAIN L. Biddlestone ° , S. Dolan. Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow, UK Recent studies in vitro suggest that Gingko biloba has anti-inflammatory properties but analgesic properties are unknown. The aim of this study is to determine if Ginkgo biloba extract, EGb-761 (gifted from Dr Schwabe Pharmaceuticals) is analgesic in an animal model of post-surgical pain. Adult male Wistar rats (n = 6/group; 250–310 g) were anaesthetised with isoflurane and a longitudal 1 cm incision was made through the skin, fascia and plantaris muscle of the hindpaw. Control animals were subjected to anaesthesia only (n = 7). Hindpaw withdrawal latency (in secs) to thermal stimulation and response threshold (in grams) to mechanical stimulation were measured before surgery and at 2, 4, 6 h, and 1, 2, 3 and 8 days after surgery. The effect of oral administration of Ginkgo biloba extract (30, 100 and 300 mg/g) or drug-vehicle at 3 h post-surgery on response thresholds were assessed. Data are mean maximum decrease (%) from baseline ± SEM. Drug-vehicle treated animals displayed maximum thermal hyperalgesia (56.9±4.0%; p < 0.001) and mechanical allodynia (45.4±4.8%; p < 0.001) 6 h post-surgery. Administration of Ginkgo biloba (30, 100 and 300 mg/kg) blocked thermal hyperalgesia at 6 h (22.6±5.1%, 12.0±5.4% and 6.9±4.7%; respectively; p < 0.001 vs. vehicle). Administration of Ginkgo biloba had no effect on mechanical allodynia. These results demonstrate that Ginkgo biloba has significant analgesic activity in this model, suggesting that it may be a useful therapeutic agent for the treatment of surgical pain.
316 COMPARISON OF CAUDAL EPIDURAL ANESTHESIA WITH LIDOCAINE-DISTILLED WATER AND LIDOCAINE-MGSO4 MIXTURE IN DOGS A. Bigham Sadegh ° , S. Dehghani, Z. Shafiei. Department of Veterinary Surgery, Veterinary Medicine School, Shiraz University, Shiraz, Iran Objective: To directly compare the time to recumbency, onset, duration of analgesia and standing produced by a Lidocaine-MgSO4 combination with that produced by Lidocaine-Distilled water administration in the caudal epidural space of indigenous awake dogs. Animal Five (<1 year old) female indigenous dogs weighting (10.74±0.44 kg). Methods: Epidural anesthesia was produced in all dogs with 2% lidocaine (1 ml/4.5 kg body weight) with 1 ml distilled water and two weeks later repeated by lidocaine (1 ml/4.5 kg) with 1 ml of 10% MgSO4. Time to recumbency, onset, duration of analgesia and cranial spread of analgesia with standing time were recorded. Heart rate, Respiratory rate and body temperature were recorded at 0 minute prior to epidural administrations of each treatments as a base line values and at 5, 10, 15, 30, 60 and 75 minutes after the epidural administrations. Statistical