- Email: [email protected]
F171 PHARMACOLOGICAL EVALUATION OF A NEW CAPSAICIN MODEL WHICH INDUCES SECONDARY HYPERALGESIA, SECONDARY ALLODYNIA AND ONGOING PAIN IN HEALTHY VOLUNTEERS
POSTER SESSIONS / European Journal of Pain Supplements 5 (2011) 15–295
were investigated with pretreatment: naloxone (2 mg/kg) opioid receptor antagonist; CTOP (1 mg/kg) m-opioid receptor antagonist; binaltorphimine (10 mg/kg) selective ú-opioid receptor antagonist; naltrindole (1 mg/kg) selective d-opioid antagonist; flumazenil (20 mg/kg) benzodiazepine antagonist. Neuropathic pain was induced in male Wistar rats which were submitted to a chronic constrictive injury (CCI) and the thermal hyperalgesia was determined. Results: The reactivity of animals in the neurogenic phase of the formalin test was reduced in a dose-dependent manner, from 51.5±5.5 to 49.0±3.5; 38.4±5.5 (P < 0.05) and 30.8±3.4 s (P < 0.05) after administration of 2, 3 and 4 mg/kg of LASSBio1410. The antinociceptive activity was reversed by naloxone, flumazenil and naltrindole. The reactivity was 55.2±4.4; 63.7±8.1 s and 55.8±5.7 s after pretreatment of naloxone, flumazenil and naltrindole. Reactivity was also reduced in the inflammatory phase. Seven days after the CCI, the injury produced hyperalgesia because it significantly decreased the withdrawal of hind paw from 8.7±0.6 s to 5.2±0.6 s which was reversed by LASSBio-1410 (7.9±0.7, P < 0.05). Conclusions: LASSBio-1410 promoted antinociception in inflammatory pain model mediated by activation of GABAergic and opioid type delta receptors and prevented hyperalgesia in neuropathic pain model. Disclosure: None declared
F170 REDUCTION OF HYPERALGESIA AND ALLODYNIA ON PERIPHERAL NEUROPATHY IN RATS BY A NEW ANTINOCICEPTIVE AGENT T.C.F. Mendes1 *, F. Antunes2 , N.M. Nascimento-Junior3 , C.A.M. Fraga4 , E.J. Barreiro4 , R.T. Sudo1 , G. Zapata-Sudo1 . 1 Farmacologia B´ asica e Cl´ınica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 2 Centro de Ciˆencia e Tecnologia Agropecu´ aria, Universidade Estadual Norte Fluminense, Campos dos Goytacazes, 3 Instituto de Qu´ımica, 4 Faculdade de Farm´ acia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil Background and Aims: New pirazol[3,4-b]pirrol[3,4-d]piridine derivatives, as LASSBio-873, promotes significant antinociceptive activity through activation of cholinergic system. Based on this, LASSBio-873 was tested in animal model of chronic pain using spinal nerve ligation (SNL). Methods: SNL was used to induce peripheral neuropathy in male Wistar rats (180–200 g). Four hours (preventive protocol) or 7 days after surgery (therapeutic protocol), LASSBio-873 (100 mg/kg, per orum) was administered daily for 7 days. Thermal sensitivity and mechanical allodynia were assessed using the plantar analgesia meter and digital analgesia meter (Von Frey test). This study was performed in compliance with the Animal Care and Use Committee at Universidade Federal do Rio de Janeiro (UFRJ). Results: LASSBio-873 (100 mg/kg, p.o.) inhibited the development of heat hyperalgesia and mechanical allodynia. In the preventive protocol, LASSBio-873 significantly increased the withdrawal of hind paw from 8.9±0.7 to 10.7±0.6 s and from 32.2±0.9 g to 34.7±2.3 g. In the therapeutic protocol, animals that developed hyperalgesia and allodynia were treated and LASSBio-873 recovered latency back to control values in SNL group. Latency for hyperalgesia was altered from 5.6±0.4 to 10.4±0.3 s after treatment with LASSBio-873. In mechanical allodynia, the control latency 32.2±0.7 g was reduced to 21.0±1.3 g after SNL and was recovery to 33.2±1.0 g, 7 days after LASSBio-873 treatment. Conclusions: Lassbio-873 could abolish the development of allodynia and heat hyperalgesia induced by SNL in rats. Disclosure: CNPQ, FAPERJ, FUJB, INCT, CAPES, PENSA RIO, PRONEX
123
F171 PHARMACOLOGICAL EVALUATION OF A NEW CAPSAICIN MODEL WHICH INDUCES SECONDARY HYPERALGESIA, SECONDARY ALLODYNIA AND ONGOING PAIN IN HEALTHY VOLUNTEERS W. Timmerman1 *, M. Harbers2 , K.H. Konopka3 , R. Kortekaas4 , A.A. van Vliet1 , M. van Wijhe3 , J.A. den Boer2 , A. Houghton5 . 1 Scientific Affaires, PRA International, Zuidlaren, 2 Department of Psychiatry, 3 Pain Management Unit, Department of Anesthesiology, 4 NeuroImaging Center, Department of Neuroscience, University Medical Center Groningen, Groningen, The Netherlands, 5 Merck, West Point, PA, USA Background and Aims: To predict the efficacy of novel analgesics in an early stage of drug development, experimental pain models in healthy volunteers are often used. We have developed a new experimental model for neuropathic pain, the Heat Capsaicin Warmth model (HCW model), that not only mimics hyperalgesia and allodynia as characteristic features of neuropathic pain, but also background pain. We hypothesized that drugs which are known to be efficacious in the treatment of neuropathic pain also affect the sensory changes induced by the HCW model. Methods: In a three-way crossover study, 24 healthy volunteers underwent a sensitization procedure, i.e. 5 min heat stimulation (45°C) followed by topical application of capsaicin (0.3%) and concomitant warmth stimulation (37°C) in each period. Doubleblind and randomized, a single dose of gabapentin (1200 mg oral), a remifentanil infusion (0.05 mg/kg/min) and placebo treatment were administered with 14 days washout between treatments. Primary endpoints were the extent of secondary hyperalgesia, allodynia and the intensity of background pain. Results: Gabapentin inhibited the development of secondary hyperalgesia and allodynia but had only limited effect on background pain. Remifentanil infusion reduced background pain, reduced the extent of secondary allodynia, but not the extent of hyperalgesia. Conclusions: Gabapentin and remifentanil showed differential effects on secondary hyperalgesia, allodynia and background pain in our newly developed human experimental model for neuropathic pain. We conclude that the HCW model has the essay sensitivity required to show efficacy of novel compounds at an early stage of the drug development. Disclosure: This work is done by a consortium of academic and industrial partners
F172 RELIABILITY OF QUANTITATIVE SENSORY TESTING IN A LOW BACK PAIN POPULATION P.H. Vuilleumier *, S. Mlekusch, A. Siegenthaler, M. Curatolo. Universit¨ atsklinik f¨ ur An¨ asthesiologie und Schmerztherapie, Universit¨ atsspital Bern, Bern, Switzerland Background and Aims: Reliability is an essential condition for using quantitative sensory tests (QST) in research and clinical practice, but information on chronic pain patients is sparse. The aim of this study is to evaluate the reliability of different QST assessments in chronic low back pain patients. Methods: The first 19 patients were included in this preliminary analysis. Patients received QST on two different sessions: pressure, electrical, heat and cold stimulation, and conditioned pain modulation using ice water (CPM). The data were analyzed with Pearson product moment correlation. Results: The correlation coefficients (p-values) were: pressure pain detection threshold 0.75 (0.0002), pressure pain tolerance threshold 0.75 (0.0002), electric pain single stimulation threshold 0.49 (0.0337), electric pain temporal summation threshold 0.32 (0.189), NRS at supra-threshold electric temporal summation 0.75 (0.0002), heat pain detection threshold 0.33 (0.168), heat pain tolerance threshold 0.72 (0.0006), cold pain detection threshold 0.51 (0.0271), time to reach NRS 7 in ice-water 0.89 (0.0000), CPM
were investigated with pretreatment: naloxone (2 mg/kg) opioid receptor antagonist; CTOP (1 mg/kg) m-opioid receptor antagonist; binaltorphimine (10 mg/kg) selective ú-opioid receptor antagonist; naltrindole (1 mg/kg) selective d-opioid antagonist; flumazenil (20 mg/kg) benzodiazepine antagonist. Neuropathic pain was induced in male Wistar rats which were submitted to a chronic constrictive injury (CCI) and the thermal hyperalgesia was determined. Results: The reactivity of animals in the neurogenic phase of the formalin test was reduced in a dose-dependent manner, from 51.5±5.5 to 49.0±3.5; 38.4±5.5 (P < 0.05) and 30.8±3.4 s (P < 0.05) after administration of 2, 3 and 4 mg/kg of LASSBio1410. The antinociceptive activity was reversed by naloxone, flumazenil and naltrindole. The reactivity was 55.2±4.4; 63.7±8.1 s and 55.8±5.7 s after pretreatment of naloxone, flumazenil and naltrindole. Reactivity was also reduced in the inflammatory phase. Seven days after the CCI, the injury produced hyperalgesia because it significantly decreased the withdrawal of hind paw from 8.7±0.6 s to 5.2±0.6 s which was reversed by LASSBio-1410 (7.9±0.7, P < 0.05). Conclusions: LASSBio-1410 promoted antinociception in inflammatory pain model mediated by activation of GABAergic and opioid type delta receptors and prevented hyperalgesia in neuropathic pain model. Disclosure: None declared
F170 REDUCTION OF HYPERALGESIA AND ALLODYNIA ON PERIPHERAL NEUROPATHY IN RATS BY A NEW ANTINOCICEPTIVE AGENT T.C.F. Mendes1 *, F. Antunes2 , N.M. Nascimento-Junior3 , C.A.M. Fraga4 , E.J. Barreiro4 , R.T. Sudo1 , G. Zapata-Sudo1 . 1 Farmacologia B´ asica e Cl´ınica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 2 Centro de Ciˆencia e Tecnologia Agropecu´ aria, Universidade Estadual Norte Fluminense, Campos dos Goytacazes, 3 Instituto de Qu´ımica, 4 Faculdade de Farm´ acia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil Background and Aims: New pirazol[3,4-b]pirrol[3,4-d]piridine derivatives, as LASSBio-873, promotes significant antinociceptive activity through activation of cholinergic system. Based on this, LASSBio-873 was tested in animal model of chronic pain using spinal nerve ligation (SNL). Methods: SNL was used to induce peripheral neuropathy in male Wistar rats (180–200 g). Four hours (preventive protocol) or 7 days after surgery (therapeutic protocol), LASSBio-873 (100 mg/kg, per orum) was administered daily for 7 days. Thermal sensitivity and mechanical allodynia were assessed using the plantar analgesia meter and digital analgesia meter (Von Frey test). This study was performed in compliance with the Animal Care and Use Committee at Universidade Federal do Rio de Janeiro (UFRJ). Results: LASSBio-873 (100 mg/kg, p.o.) inhibited the development of heat hyperalgesia and mechanical allodynia. In the preventive protocol, LASSBio-873 significantly increased the withdrawal of hind paw from 8.9±0.7 to 10.7±0.6 s and from 32.2±0.9 g to 34.7±2.3 g. In the therapeutic protocol, animals that developed hyperalgesia and allodynia were treated and LASSBio-873 recovered latency back to control values in SNL group. Latency for hyperalgesia was altered from 5.6±0.4 to 10.4±0.3 s after treatment with LASSBio-873. In mechanical allodynia, the control latency 32.2±0.7 g was reduced to 21.0±1.3 g after SNL and was recovery to 33.2±1.0 g, 7 days after LASSBio-873 treatment. Conclusions: Lassbio-873 could abolish the development of allodynia and heat hyperalgesia induced by SNL in rats. Disclosure: CNPQ, FAPERJ, FUJB, INCT, CAPES, PENSA RIO, PRONEX
123
F171 PHARMACOLOGICAL EVALUATION OF A NEW CAPSAICIN MODEL WHICH INDUCES SECONDARY HYPERALGESIA, SECONDARY ALLODYNIA AND ONGOING PAIN IN HEALTHY VOLUNTEERS W. Timmerman1 *, M. Harbers2 , K.H. Konopka3 , R. Kortekaas4 , A.A. van Vliet1 , M. van Wijhe3 , J.A. den Boer2 , A. Houghton5 . 1 Scientific Affaires, PRA International, Zuidlaren, 2 Department of Psychiatry, 3 Pain Management Unit, Department of Anesthesiology, 4 NeuroImaging Center, Department of Neuroscience, University Medical Center Groningen, Groningen, The Netherlands, 5 Merck, West Point, PA, USA Background and Aims: To predict the efficacy of novel analgesics in an early stage of drug development, experimental pain models in healthy volunteers are often used. We have developed a new experimental model for neuropathic pain, the Heat Capsaicin Warmth model (HCW model), that not only mimics hyperalgesia and allodynia as characteristic features of neuropathic pain, but also background pain. We hypothesized that drugs which are known to be efficacious in the treatment of neuropathic pain also affect the sensory changes induced by the HCW model. Methods: In a three-way crossover study, 24 healthy volunteers underwent a sensitization procedure, i.e. 5 min heat stimulation (45°C) followed by topical application of capsaicin (0.3%) and concomitant warmth stimulation (37°C) in each period. Doubleblind and randomized, a single dose of gabapentin (1200 mg oral), a remifentanil infusion (0.05 mg/kg/min) and placebo treatment were administered with 14 days washout between treatments. Primary endpoints were the extent of secondary hyperalgesia, allodynia and the intensity of background pain. Results: Gabapentin inhibited the development of secondary hyperalgesia and allodynia but had only limited effect on background pain. Remifentanil infusion reduced background pain, reduced the extent of secondary allodynia, but not the extent of hyperalgesia. Conclusions: Gabapentin and remifentanil showed differential effects on secondary hyperalgesia, allodynia and background pain in our newly developed human experimental model for neuropathic pain. We conclude that the HCW model has the essay sensitivity required to show efficacy of novel compounds at an early stage of the drug development. Disclosure: This work is done by a consortium of academic and industrial partners
F172 RELIABILITY OF QUANTITATIVE SENSORY TESTING IN A LOW BACK PAIN POPULATION P.H. Vuilleumier *, S. Mlekusch, A. Siegenthaler, M. Curatolo. Universit¨ atsklinik f¨ ur An¨ asthesiologie und Schmerztherapie, Universit¨ atsspital Bern, Bern, Switzerland Background and Aims: Reliability is an essential condition for using quantitative sensory tests (QST) in research and clinical practice, but information on chronic pain patients is sparse. The aim of this study is to evaluate the reliability of different QST assessments in chronic low back pain patients. Methods: The first 19 patients were included in this preliminary analysis. Patients received QST on two different sessions: pressure, electrical, heat and cold stimulation, and conditioned pain modulation using ice water (CPM). The data were analyzed with Pearson product moment correlation. Results: The correlation coefficients (p-values) were: pressure pain detection threshold 0.75 (0.0002), pressure pain tolerance threshold 0.75 (0.0002), electric pain single stimulation threshold 0.49 (0.0337), electric pain temporal summation threshold 0.32 (0.189), NRS at supra-threshold electric temporal summation 0.75 (0.0002), heat pain detection threshold 0.33 (0.168), heat pain tolerance threshold 0.72 (0.0006), cold pain detection threshold 0.51 (0.0271), time to reach NRS 7 in ice-water 0.89 (0.0000), CPM