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296 A NEW ARYLPIPERAZINYLALKYL DERIVATIVE WITH POTENT ANTINOCICEPTIVE ACTIVITY IN MICE
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Poster Sessions / European Journal of Pain 13 (2009) S55–S285
296 A NEW ARYLPIPERAZINYLALKYL DERIVATIVE WITH POTENT ANTINOCICEPTIVE ACTIVITY IN MICE M. Mastriota1 , A. Di Giannuario1 , M. Colucci1 , M.P. Giovannoni2 , C. Biancalani2 , V. Dal Piaz2 , S. Pieretti1 *. 1 Istituto Superiore di Sanit` a, Rome, Italy; 2 Department of Pharmaceutical Sciences, University of Florence, Sesto F.no, Florence, Italy Background and Aims: Our effort in the field of the analgesic agents recently produced a large number of molecules with pyridazine scaffold showing an interesting level of antinociceptive potency (for a review see Giovannoni et al., Med Res Rev. 29:339–68, 2009). In this study we examined the antinociceptive activity in mice of a new arylpiperazinylalkyl derivative named ET1. Methods: Nociception was induced by using thermal (hot plate and tail flick test) or chemical (formalin test) nociceptive stimuli and ET1 effect on nociceptive threshold was evaluated after central or peripheral administration in mice. Results: ET1 centrally or orally administered potently reduced the behavioral responses to thermal nociceptive stimuli in mice. ET1 also reduced the licking behavior in the formalin test after local administration in the mice paw. ET1 effects were antagonized by an ineffective dose of the a2 -adrenergic antagonist yohimbine. Conclusions: Our observations suggest the possible involvement of adrenergic system in ET1 effects and that ET1 may be further developed as analgesic drug. 297 INVESTIGATION OF THE ROLE OF FORMYL PEPTIDE RECEPTOR IN ACUTE NOCICEPTION USING GENE-DEFICIENT MICE S. Pieretti1 *, A. Di Giannuario1 , M. Colucci1 , M. Mastriota1 , M. Perretti2 . 1 Istituto Superiore di Sanit` a, Rome, Italy; 2 William Harvey Research Institute, Barts and The London, School of Medicine, LONDON, Great Britain Background and Aims: Formyl peptide receptors (FPRs) are Gi protein-coupled chemoattractant receptors expressed primarily in phagocytes. In the 1999, a novel colony of mice lacking the high affinity N-formyl peptide receptor (FPR) was created by targeted gene disruption (Gao et al., J.Exp.Med. 189:657–662, 1999). FPR knockout (KO) mice develop normally, but have increased mortality to Listeria monocytogenes compared with wild-type (WT) littermates. Since the FPR agonist fMLF and the fragment aminoacid 2–26 of the endogenous protein Annexin A1 induced antinociceptive effects in a model of acute inflammatory model as the formalin test in CD-1 mice (Pieretti et al., Pain 109:52–63, 2004), we tested here the role of endogenous FPR role in acute nociception was analysed by comparison to WT mice. Methods: Nociception was induced by using thermal (hot plate and tail flick test) or chemical (formalin test) nociceptive stimuli, and the nociceptive threshold was recorded in male FPRKO and in WT mice. Results: FPRKO and WT mice were not different in the behavioural response to thermal stimuli in the hot plate and tail flick test. In the inflammatory phase of the formalin test – occurring from 20 to 40 min after formalin injection – a strong increase in the nocifensive behaviour was observed in the FPRKO mice. This increase did not change after FPR agonists administration in FPRKO mice. Conclusion. These results suggest an involvement of FPR in pain induced by acute-inflammatory nociceptive stimuli in mice and might indicate a new way to treat pain evoked by inflammatory stimuli in man. 298 CYTOKINES SERUM LEVELS IN CHRONIC LOW BACK PAIN DUE TO HERNIATED DISK D. Kraychete *, R. Sakata, A. Issy, E. Carvalho. Universidade Federal de S˜ ao Paulo, S˜ ao Paulo, Brazil Background and Objective: The role of immune response and proinflammatory cytokines in the pathogenesis of chronic pain has
been a subject of increasing interest. In order to evaluate if there is an association between elevated levels of cytokines and chronic pain due to herniated disk disease, we measured cytokines levels in patients with chronic low back pain and in a group of healthy subjects. Methods: Serum levels of pro-inflammatory cytokines were measured using the Enzyme Linked Immuno Sorbent Assay (ELISA) technique in 23 patients with pain due to herniated disk disease (G1) as well as in 10 control healthy subjects (G2). Results: Tumor necrosis factor-alpha [TNF-alpha] (G1 = 5.6 ± 2.3 pg/ml, and G2 = 1.6 ± 0.5 pg/ml, p = 0.01) and interleukin-6 [IL-6] (G1 = 4.1 ± 3.0 pg/ml, and G2 = 0.9 ± 0.4 pg/ml, p = 0.01) levels were higher herniated disk patients. There was no statistically difference in interleukin-1 [IL-1] (G1 = 0.5 ± 0.3 pg/ml, and G2 = 0.5 ± 0.1 pg/ml, p = 1), and soluble tumor necrosis factor receptor [sTNF-R] (G1 = 572 pg/ml ± 36, and G2 = 581 ± 50 pg/ml, p = 0.87). Conclusion: Patients with chronic low back pain and disc herniation included in this study exhibites higher levels of TNFalpha, and IL-6, but not of IL-1, and sTNF-R when compared with healthy subjects. 299 ATTENTIONAL SWITCHING BETWEEN PAIN AND OTHER DEMANDS: APPLICATION OF A TASK SWITCHING PARADIGM D. Van Ryckeghem *, G. Crombez, B. Liefooghe, A. Vandierendonck. Ghent University, Ghent, Belgium Background and Aims: Research has demonstrated that pain strongly demands attention. Nevertheless, persons who experience pain still have to perform daily tasks. In order to do so successfully, they need to flexibly switch attention between pain and these tasks. Until now this idea has not been systematically examined. The aim of the present study was to investigate attentional switching between pain and other demands by means of a task switching paradigm. Methods: Thirty undergraduate students performed a task switching paradigm. Participants constantly needed to repeat, or switch between, three different reaction time tasks (responding to form, colour, or direction of visual stimuli). In one of the three tasks a painful stimulus was sometimes administered, as a result of which this became a pain-related task. We compared performance on trials in which a neutral task was preceded by the pain-related task with trials in which a neutral task was preceded by another neutral task. Results: Participants were significantly slower when they had to switch from the pain-related task to a neutral task (M = 710 ms; SD = 160), than when they had to switch between two neutral tasks (M = 667 ms; SD = 129), (t(29) = −3.37, p < 0.01). Conclusions: The results show that it is more difficult to switch attention away from a pain-related task, than to switch attention away from a neutral task. Our task switching paradigm might be a useful tool to investigate which factors influence the ability to flexibly switch between pain and other demands. 300 SPHINGOSINE-1-PHOSPHATE INDUCES HEAT HYPERALGESIA IN C57BL6J MICE C. Benetti1 *, N. Mair1 , M.G. Leitner1 , C.E. Costantin1 , M. Andratsch1 , R. Haberberger2 , M. Kress1 . 1 Division of Physiology, Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria; 2 Anatomy and Histology, Flinders University, Adelaide, Australia Sphingosine 1-phosphate (S1P) is an important lipid mediator regulating inflammatory processes. However, its role in the development of inflammatory pain is little understood. We therefore studied if S1P can induce nociceptive responses in vivo and in vitro and address the mechanisms that could be involved.
Poster Sessions / European Journal of Pain 13 (2009) S55–S285
296 A NEW ARYLPIPERAZINYLALKYL DERIVATIVE WITH POTENT ANTINOCICEPTIVE ACTIVITY IN MICE M. Mastriota1 , A. Di Giannuario1 , M. Colucci1 , M.P. Giovannoni2 , C. Biancalani2 , V. Dal Piaz2 , S. Pieretti1 *. 1 Istituto Superiore di Sanit` a, Rome, Italy; 2 Department of Pharmaceutical Sciences, University of Florence, Sesto F.no, Florence, Italy Background and Aims: Our effort in the field of the analgesic agents recently produced a large number of molecules with pyridazine scaffold showing an interesting level of antinociceptive potency (for a review see Giovannoni et al., Med Res Rev. 29:339–68, 2009). In this study we examined the antinociceptive activity in mice of a new arylpiperazinylalkyl derivative named ET1. Methods: Nociception was induced by using thermal (hot plate and tail flick test) or chemical (formalin test) nociceptive stimuli and ET1 effect on nociceptive threshold was evaluated after central or peripheral administration in mice. Results: ET1 centrally or orally administered potently reduced the behavioral responses to thermal nociceptive stimuli in mice. ET1 also reduced the licking behavior in the formalin test after local administration in the mice paw. ET1 effects were antagonized by an ineffective dose of the a2 -adrenergic antagonist yohimbine. Conclusions: Our observations suggest the possible involvement of adrenergic system in ET1 effects and that ET1 may be further developed as analgesic drug. 297 INVESTIGATION OF THE ROLE OF FORMYL PEPTIDE RECEPTOR IN ACUTE NOCICEPTION USING GENE-DEFICIENT MICE S. Pieretti1 *, A. Di Giannuario1 , M. Colucci1 , M. Mastriota1 , M. Perretti2 . 1 Istituto Superiore di Sanit` a, Rome, Italy; 2 William Harvey Research Institute, Barts and The London, School of Medicine, LONDON, Great Britain Background and Aims: Formyl peptide receptors (FPRs) are Gi protein-coupled chemoattractant receptors expressed primarily in phagocytes. In the 1999, a novel colony of mice lacking the high affinity N-formyl peptide receptor (FPR) was created by targeted gene disruption (Gao et al., J.Exp.Med. 189:657–662, 1999). FPR knockout (KO) mice develop normally, but have increased mortality to Listeria monocytogenes compared with wild-type (WT) littermates. Since the FPR agonist fMLF and the fragment aminoacid 2–26 of the endogenous protein Annexin A1 induced antinociceptive effects in a model of acute inflammatory model as the formalin test in CD-1 mice (Pieretti et al., Pain 109:52–63, 2004), we tested here the role of endogenous FPR role in acute nociception was analysed by comparison to WT mice. Methods: Nociception was induced by using thermal (hot plate and tail flick test) or chemical (formalin test) nociceptive stimuli, and the nociceptive threshold was recorded in male FPRKO and in WT mice. Results: FPRKO and WT mice were not different in the behavioural response to thermal stimuli in the hot plate and tail flick test. In the inflammatory phase of the formalin test – occurring from 20 to 40 min after formalin injection – a strong increase in the nocifensive behaviour was observed in the FPRKO mice. This increase did not change after FPR agonists administration in FPRKO mice. Conclusion. These results suggest an involvement of FPR in pain induced by acute-inflammatory nociceptive stimuli in mice and might indicate a new way to treat pain evoked by inflammatory stimuli in man. 298 CYTOKINES SERUM LEVELS IN CHRONIC LOW BACK PAIN DUE TO HERNIATED DISK D. Kraychete *, R. Sakata, A. Issy, E. Carvalho. Universidade Federal de S˜ ao Paulo, S˜ ao Paulo, Brazil Background and Objective: The role of immune response and proinflammatory cytokines in the pathogenesis of chronic pain has
been a subject of increasing interest. In order to evaluate if there is an association between elevated levels of cytokines and chronic pain due to herniated disk disease, we measured cytokines levels in patients with chronic low back pain and in a group of healthy subjects. Methods: Serum levels of pro-inflammatory cytokines were measured using the Enzyme Linked Immuno Sorbent Assay (ELISA) technique in 23 patients with pain due to herniated disk disease (G1) as well as in 10 control healthy subjects (G2). Results: Tumor necrosis factor-alpha [TNF-alpha] (G1 = 5.6 ± 2.3 pg/ml, and G2 = 1.6 ± 0.5 pg/ml, p = 0.01) and interleukin-6 [IL-6] (G1 = 4.1 ± 3.0 pg/ml, and G2 = 0.9 ± 0.4 pg/ml, p = 0.01) levels were higher herniated disk patients. There was no statistically difference in interleukin-1 [IL-1] (G1 = 0.5 ± 0.3 pg/ml, and G2 = 0.5 ± 0.1 pg/ml, p = 1), and soluble tumor necrosis factor receptor [sTNF-R] (G1 = 572 pg/ml ± 36, and G2 = 581 ± 50 pg/ml, p = 0.87). Conclusion: Patients with chronic low back pain and disc herniation included in this study exhibites higher levels of TNFalpha, and IL-6, but not of IL-1, and sTNF-R when compared with healthy subjects. 299 ATTENTIONAL SWITCHING BETWEEN PAIN AND OTHER DEMANDS: APPLICATION OF A TASK SWITCHING PARADIGM D. Van Ryckeghem *, G. Crombez, B. Liefooghe, A. Vandierendonck. Ghent University, Ghent, Belgium Background and Aims: Research has demonstrated that pain strongly demands attention. Nevertheless, persons who experience pain still have to perform daily tasks. In order to do so successfully, they need to flexibly switch attention between pain and these tasks. Until now this idea has not been systematically examined. The aim of the present study was to investigate attentional switching between pain and other demands by means of a task switching paradigm. Methods: Thirty undergraduate students performed a task switching paradigm. Participants constantly needed to repeat, or switch between, three different reaction time tasks (responding to form, colour, or direction of visual stimuli). In one of the three tasks a painful stimulus was sometimes administered, as a result of which this became a pain-related task. We compared performance on trials in which a neutral task was preceded by the pain-related task with trials in which a neutral task was preceded by another neutral task. Results: Participants were significantly slower when they had to switch from the pain-related task to a neutral task (M = 710 ms; SD = 160), than when they had to switch between two neutral tasks (M = 667 ms; SD = 129), (t(29) = −3.37, p < 0.01). Conclusions: The results show that it is more difficult to switch attention away from a pain-related task, than to switch attention away from a neutral task. Our task switching paradigm might be a useful tool to investigate which factors influence the ability to flexibly switch between pain and other demands. 300 SPHINGOSINE-1-PHOSPHATE INDUCES HEAT HYPERALGESIA IN C57BL6J MICE C. Benetti1 *, N. Mair1 , M.G. Leitner1 , C.E. Costantin1 , M. Andratsch1 , R. Haberberger2 , M. Kress1 . 1 Division of Physiology, Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria; 2 Anatomy and Histology, Flinders University, Adelaide, Australia Sphingosine 1-phosphate (S1P) is an important lipid mediator regulating inflammatory processes. However, its role in the development of inflammatory pain is little understood. We therefore studied if S1P can induce nociceptive responses in vivo and in vitro and address the mechanisms that could be involved.