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T117 THE ROLE OF SPINAL GLUTAMATE UPTAKE VIA GLUTAMATE TRANSPORTER FOR INCISION-INDUCED PAIN BEHAVIORS IN RATS
POSTER SESSIONS / European Journal of Pain Supplements 5 (2011) 15–295
19
Sedlmeier and Thomas Peters are paid employees of Ingenium Pharmaceuticals GmbH.
Supported by FCT grants PTDC-SAUNEU-101995–2008, SFRH-BD28752–2006.
T114 NAV 1.9 IS A TRANSFORMATION AMPLIFIER REDUCING POLYMODAL RECEPTIVE THRESHOLDS T. Hoffmann *, K. Kistner, P. Reeh, C. Weidner. Physiology and Pathophysiology, University of Erlangen-Nuremberg, Erlangen, Germany
Disclosure: None declared
The TTX resistant (TTXr) sodium channel Nav 1.9 has previously been connected to nerve lesions induced hyperexcitability as well as inflammation related pathologies. By means of electrophysiological methods well as neuropeptide release methods we show here for the first time that also naive Nav 1.9 knocked out (KO) mice have impaired mechanical and thermal sensory capacities in comparison to control animals. In single fiber experiments the median v. Frey mechanical threshold was increased from 8 mN in the control group to 32 mN in Nav 1.9 KO mice. In addition, the abundance of C mechano heat sensitive fibers (CMH) was reduced from 76% in the control group to 10% in Nav 1.9 KO animals. The averaged heat threshold measured for the CMH fibers was 40±04°C and 44±08°C in the control and KO group, respectively. Furthermore, compound action potential measurements of nerve trunks from Nav 1.9 KO mice revealed lower heat induced slowing in comparison to control group nerves: 8±2.8% vs. 30.1±5%, respectively. Heat induced CGRP release was lower in KO animals; 45.8±1.4 pg/ml in comparison to 68±1.9 pg/ml in the control group. Hence, we show that Nav 1.9 is important for thermal and mechanical sensitivity in naive mice. We thus hypothesise that Nav 1.9 acts as a transformation amplifier of receptor potentials independent of the received stimulus. Disclosure: None declared
T115 PAIN MODELS DIFFERENTIALLY INDUCE EXPRESSION OF THE HOMEOBOX GENE PRRXL1 IN BOTH PEPTIDERGIC AND NON-PEPTIDERGIC DRG NEURONS C. Monteiro1,2 *, M. Matos1,2 , S. Rebelo1,2 , V. Galhardo1,2 , D. Lima1,2 , C. Reguenga1,2 . 1 Departamento Biologia Experimental, Faculdade de Medicina do Porto, 2 IBMC – Instituto Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal Background and Aims: Prrxl1 (also known as Drg11) is a pairedtype homeodomain transcription factor that functions as a key regulator of the differentiation and survival of nociceptive neurons in pre- and perinatal stages. Prrxl1−/− mice show diminished responses to nociceptive stimuli, as well as alterations in the adult morphology of the spinal cord dorsal horn and trigeminal nuclei; however, it is still undetermined the role this gene plays in nociceptive processing. Methods: Peripheral inflammatory pain was induced by hindpaw plantar injection of zymosan (10 mg/ml) (n = 7). Prolonged neuropathic pain was induced by the Spared Nerve Injury – SNI model (n = 7). After 4 hours (zymosan) or 7 days (SNI) the animals were sacrificed and L4-L5 DRG ipsi- and contralateral to the procedure were removed for analysis of gene expression using Real-Time PCR. Results: We show that the expression of Prrxl1 in dorsal root ganglia is maintained during adult life, persisting at 11% of the maximum expression rate, observed in E14.5. The expression of Prrxl1 mRNA in mice with zymosan-induced peripheral inflammation presented a 3.06±0.71 fold-increase in ipsilateral ganglia, which was significantly different from control animals. In contrast, a non-statistically significant decrease was detected in the SNI model of neuropathy. Triple immunostaining for Prrxl1, IB4 and CGRP showed that neurons Prrxl1-positive in inflammatory pain conditions belonged to both the peptidergic and non-peptidergic ganglionar populations. Conclusions: Our present results point to a role for Prrxl1 in sensitization of nociceptive neurons upon inflammatory pain.
T116 DIFFERENCES IN PERCEPTION AND BRAIN ACTIVATION FOLLOWING STIMULATION BY LARGE VERSUS SMALL AREA CUTANEOUS SURFACE ELECTRODES D. Lelic1 *, C.D. Morch2 , K. Hennings1 , O.K. Andersen2 , A.M. Drewes1 . 1 Mech-Sense, Aalborg Hopsital, Aarhus University Hospital, 2 Center for Sensory-Motor Interactions, Aalborg University, Aalborg, Denmark Introduction: Application of electrical stimulation through conventional surface electrodes activates both non-nociceptive and nociceptive fibers. To encompass this problem, electrical stimulation through small area pin electrode was introduced where subjective description of pain quality indicated preferential activation of nociceptors. The present study aimed to show that brain areas involved in nociceptive processing are activated by stimulation through cutaneous pin electrode (CPE) to a larger extent than conventional surface electrodes. Methods: Evoked potentials (EPs) were induced by electrical stimulation through conventional surface and CPE electrodes. The EPs were recorded from 62 scalp electrodes in 12 healthy volunteers where stimulation intensity was ten times the sensory threshold. Dipolar models of brain sources were built by using the brain electrical source analysis. Results: The solution for CPE was a 5 dipole model and had a bilateral distribution. The solution for the conventional large area surface electrode was a 4 dipole model and had a more lateralised solution. The dipolar model for the CPE was very similar to that previously described to explain the topography of laser EPs. Since laser stimuli mainly activate nociceptive fibres, the strong similarity suggests that only nociceptive inputs are involved in generation of CPE evoked responses. Conclusion: The current study gives evidence that CPE activates the nociceptive brain areas to a greater extent than conventional surface electrode. Therefore, CPEs should preferentially be utilized in future studies where electrical stimuli are used to study nociception. Disclosure: None declared
T117 THE ROLE OF SPINAL GLUTAMATE UPTAKE VIA GLUTAMATE TRANSPORTER FOR INCISION-INDUCED PAIN BEHAVIORS IN RATS S. Reichl1 *, A. Boecker1 , V. Keller1 , P.K. Zahn2 , E.M. Pogatzki-Zahn1 . 1 Department of Anaesthesiology and Intensive Care, University Hospital Muenster, Muenster, 2 Ruhr-University Bochum, BG-Kliniken Bergmannsheil, Bochum, Germany Background: The glial glutamate-transporter GLAST and GLT-1 regulate extracellular concentration of glutamate and may contribute to pain after incision. We assessed the role of mitogenactivated protein kinase (MAPK) for spinal expression of GLAST and GLT-1 and pain behavior after surgical incision. Methods: Rats with intrathecal (IT) catheter (n = 122) underwent plantar incision. All rats received SB203580 (MAPK p38inhibtor; 2 mg; saline; n = 30), PD98059 (MAPK ERK-inhibitor; 2 mg; 10%DMSO; n = 33) or vehicle (n = 59) twice a day for 4 days. In these rats, mechanical withdrawal thresholds (WT, calibrated von Frey filaments), thermal withdrawal latencies (WL, Hargreaves Box) and non-evoked pain scores were re-evaluated every day, In 18 rats, expression pattern of GLAST and GLT-1 was investigated by immunohistochemistry after incision and drug administration and in 31 rats, extracellular recordings of dorsal horn neurons were performed. Results: SB203580 but not PD98059 significantly enhanced the spontaneous pain at rest after incision. WT and WL were not increased in SB203580 or PD98059 treated rats. Similar, SB203580
20
POSTER SESSIONS / European Journal of Pain Supplements 5 (2011) 15–295
but not PD98059 inhibited the upregulation of GLAST and GLT-1 in the lumbal spinal cord after incision. Spontaneous activity of deep HT-neurons but not WDR-neurons was increased in rats treated with SB203580 after incision. Conclusions: Upregulation of GLAST and GLT-1 expression after incision is modulated by activation of p38 but not by ERK; this upregulation occurs in HT neurons which are presumably responsible for non-evoked pain after incision. Thus, the blockade of this process leads to prolonged non-evoked pain behavior due to increased spontaneous activity via increased glutamate uptake in HT neurons. Disclosure: None declared
T118 THE ANTIHYPERALGESIC EFFECT OF TAPENTADOL IN DIABETIC NEUROPATHIC MICE RESULTS FROM A SYNERGISTIC INTERACTION OF SPINAL AND SUPRASPINAL MECHANISMS T. Christoph1 *, J. De Vry1 , T. Hertrampf2 , T. Tzschentke1 . 1 Global Preclinical Research and Development, Department of Pharmacology, 2 Department of Molecular Pharmacology, Gr¨ unenthal GmbH, Aachen, Germany Background and Aims: Tapentadol is a m-opioid receptor (MOR) agonist and norepinephrine reuptake inhibitor, with high efficacy in neuropathic pain models and intrinsic synergistic interaction of both mechanisms. Although it is likely that the spinal cord is an important site for this intrinsic synergy, this hypothesis has not been experimentally verified. Methods: Diabetes was induced in mice by single administration of streptozotocin. Diabetic and weight-matched non-diabetic control mice were tested for the occurrence of nocifensive reactions on a 50°C hot plate. Spinal (i.t.) and supraspinal (i.c.v.) administration of drug and/or vehicle was performed under brief ether anesthesia and nocifensive reactions were tested before and 15, 30, 45 and 60 min after drug administration. Results: In diabetic mice, tapentadol (0.1–3.16 mg/animal) showed full efficacy after i.t. as well as i.c.v. administration (ED50 : 0.42 i.t., 0.18 i.c.v.). Combined administration of equi-analgesic doses revealed spinal-supraspinal synergy (ED50 : 0.053 i.t.+i.c.v.). Likewise, morphine (0.001–10 mg/animal) showed efficacy after both routes of administration (ED50 : 0.547 i.t., 0.004 i.c.v.) and a synergistic interaction after combined spinal/supraspinal administration (ED50 : 0.014 i.t.+i.c.v.). Conclusions: Results demonstrate that tapentadol is a centrally acting analgesic with high potency after i.c.v. and i.t. administration. The 50-fold potency difference between morphine and tapentadol after supraspinal administration is similar to the difference between both molecules in affinity for the MOR. In contrast, spinal potencies of both drugs did not differ, corresponding to similar potencies after systemic administration, suggesting that spinal mechanisms play a crucial role for the intrinsic synergy of tapentadol. Disclosure: All authors are paid employees of Grunenthal ¨ GmbH, manufacturer of tapentadol.
T119 HYPERALGESIA TO SUPERFICIAL AND DEEP MECHANICAL STIMULATION WITHIN AND OUTSIDE A UVB IRRADIATED AREA S. Lo Vecchio *, T. Graven-Nielsen, S. Finocchietti, P. Gazerani, L. Arendt-Nielsen. Health Science and Technology, Aalborg Universita, Aalborg, Denmark Background and Aims: Ultraviolet B (UVB) inflammatory pain model is often used to induce a stable hyperalgesic area in human skin. The aim of the present study was to evaluate whether this model induces a state of mechanical hyperalgesia in both superficial and deep-tissue within and outside of the irradiated area. Methods: An area of 3 × 4 cm, located on mid volar forearms of 12 healthy males, was irradiated by UVB (Medlight, Germany; 3×MED: Minimal Erythema Dose). Applying quantitative sensory
assessments, mechanical pain threshold changes were detected one day after irradiation, within and outside of the irradiated area. Sensitivity to cutaneous mechanical stimuli was assessed using von Frey hairs (Somedic, Sweden) and deep-tissue pressure pain thresholds were evaluated on 12 spots (4 within and 8 outside, distant 1.5 cm from the irradiated area) by a computer-controlled pressure algometer (Aalborg University, Denmark; 1.0 cm2 flat probe). Possible relation between applied pressure intensity and pain scores on a visual analogue scale (VAS) was also evaluated. Results: Cutaneous mechanical pain thresholds were significantly decreased within and outside the irradiated area (P < 0.05). Deeptissue pressure pain thresholds also showed a widespread and significant decrease (P < 0.001). The pressure-VAS curve highlighted a left-shift both within and outside the irradiated area (P < 0.05) with a remarkable change within the area. Conclusions: Cutaneous UVB irradiation reduced superficial and deep mechanical pain thresholds illustrating the existence of both primary and secondary hyperalgesia to mechanical stimuli. Disclosure: None declared
T120 MATERNAL SEPARATION DELAYS THE FUNCTIONAL ESTABLISHMENT OF ASCENDING AND DESCENDING NOCICEPTIVE CIRCUITS IN THE RAT SPINAL CORD 1 P.-E. Juif1,2 *, N. Petit Demouliere1 , A. Lacaud1 , V. Lelievre ` , P. Darbon1 , P. Poisbeau1 . 1 Nociception & Pain, Institute of Cellular and Integrative Neurosciences, Strasbourg, France; 2 Neuropsychology, University of Luxembourg, Luxembourg, Luxembourg Background and Aims: At birth, the development of spinal nociceptive circuits is not yet achieved in rodents. Until postnatal day 14 (P14), C-fiber inputs are relatively sparse, produce weak excitation and does not contribute to wind up. Moreover, descending inhibitory pathways and among them diffuse noxious inhibitory controls (DNIC) become fully efficient at P21. Maternal separation (MS) in rats has already been shown to be associated with pain hypersensitivity at more adult stages. The goal of this study was to characterize in detail the effect of postnatal stress on the early establishment of functional C-fiber-mediated transmission and DNIC in spinal cord neurons. Methods: We used in vivo electrophysiological recordings of dorsal horn neurons in rats and behavioral tests to characterize the functional consequence of MS on nociception. Results: A fully fonctional C-fiber-mediated neurotransmission was strongly delayed after MS. Until P24, induction of DNIC in stressed rats was impossible and was even producing an excitation. DNIC was eventually recovered at a later stage suggesting that MS delays the efficacy of DNIC. Conclusions: In summary, we show that MS has major consequences on the establishment of a functional nociceptive spinal network. The underlying molecular mechanisms are currently under investigation. This study might have important implication in human studies while considering pain strategies in preterm neonates. Acknowledgments: This project is supported by the CNRS (France), the FNR (Luxembourg) and cofunded under the Marie Curie Actions of the European Commission (FP7-COFUND). Disclosure: None declared
T121 THE SPATIAL RESOLUTION OF THE NOCICEPTIVE SYSTEM: A PSYCHOPHYSICAL STUDY I. Weissman-Fogel1 *, N. Zwi2 , R. Defrin2 . 1 Department of Physical Therapy, Faculty of Social Welfare & Health Sciences, University of Haifa, Haifa, 2 Department of Physical Therapy, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel Background and Aims: Results regarding the spatial resolution of the pain system are contradictory. While microneurographic
19
Sedlmeier and Thomas Peters are paid employees of Ingenium Pharmaceuticals GmbH.
Supported by FCT grants PTDC-SAUNEU-101995–2008, SFRH-BD28752–2006.
T114 NAV 1.9 IS A TRANSFORMATION AMPLIFIER REDUCING POLYMODAL RECEPTIVE THRESHOLDS T. Hoffmann *, K. Kistner, P. Reeh, C. Weidner. Physiology and Pathophysiology, University of Erlangen-Nuremberg, Erlangen, Germany
Disclosure: None declared
The TTX resistant (TTXr) sodium channel Nav 1.9 has previously been connected to nerve lesions induced hyperexcitability as well as inflammation related pathologies. By means of electrophysiological methods well as neuropeptide release methods we show here for the first time that also naive Nav 1.9 knocked out (KO) mice have impaired mechanical and thermal sensory capacities in comparison to control animals. In single fiber experiments the median v. Frey mechanical threshold was increased from 8 mN in the control group to 32 mN in Nav 1.9 KO mice. In addition, the abundance of C mechano heat sensitive fibers (CMH) was reduced from 76% in the control group to 10% in Nav 1.9 KO animals. The averaged heat threshold measured for the CMH fibers was 40±04°C and 44±08°C in the control and KO group, respectively. Furthermore, compound action potential measurements of nerve trunks from Nav 1.9 KO mice revealed lower heat induced slowing in comparison to control group nerves: 8±2.8% vs. 30.1±5%, respectively. Heat induced CGRP release was lower in KO animals; 45.8±1.4 pg/ml in comparison to 68±1.9 pg/ml in the control group. Hence, we show that Nav 1.9 is important for thermal and mechanical sensitivity in naive mice. We thus hypothesise that Nav 1.9 acts as a transformation amplifier of receptor potentials independent of the received stimulus. Disclosure: None declared
T115 PAIN MODELS DIFFERENTIALLY INDUCE EXPRESSION OF THE HOMEOBOX GENE PRRXL1 IN BOTH PEPTIDERGIC AND NON-PEPTIDERGIC DRG NEURONS C. Monteiro1,2 *, M. Matos1,2 , S. Rebelo1,2 , V. Galhardo1,2 , D. Lima1,2 , C. Reguenga1,2 . 1 Departamento Biologia Experimental, Faculdade de Medicina do Porto, 2 IBMC – Instituto Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal Background and Aims: Prrxl1 (also known as Drg11) is a pairedtype homeodomain transcription factor that functions as a key regulator of the differentiation and survival of nociceptive neurons in pre- and perinatal stages. Prrxl1−/− mice show diminished responses to nociceptive stimuli, as well as alterations in the adult morphology of the spinal cord dorsal horn and trigeminal nuclei; however, it is still undetermined the role this gene plays in nociceptive processing. Methods: Peripheral inflammatory pain was induced by hindpaw plantar injection of zymosan (10 mg/ml) (n = 7). Prolonged neuropathic pain was induced by the Spared Nerve Injury – SNI model (n = 7). After 4 hours (zymosan) or 7 days (SNI) the animals were sacrificed and L4-L5 DRG ipsi- and contralateral to the procedure were removed for analysis of gene expression using Real-Time PCR. Results: We show that the expression of Prrxl1 in dorsal root ganglia is maintained during adult life, persisting at 11% of the maximum expression rate, observed in E14.5. The expression of Prrxl1 mRNA in mice with zymosan-induced peripheral inflammation presented a 3.06±0.71 fold-increase in ipsilateral ganglia, which was significantly different from control animals. In contrast, a non-statistically significant decrease was detected in the SNI model of neuropathy. Triple immunostaining for Prrxl1, IB4 and CGRP showed that neurons Prrxl1-positive in inflammatory pain conditions belonged to both the peptidergic and non-peptidergic ganglionar populations. Conclusions: Our present results point to a role for Prrxl1 in sensitization of nociceptive neurons upon inflammatory pain.
T116 DIFFERENCES IN PERCEPTION AND BRAIN ACTIVATION FOLLOWING STIMULATION BY LARGE VERSUS SMALL AREA CUTANEOUS SURFACE ELECTRODES D. Lelic1 *, C.D. Morch2 , K. Hennings1 , O.K. Andersen2 , A.M. Drewes1 . 1 Mech-Sense, Aalborg Hopsital, Aarhus University Hospital, 2 Center for Sensory-Motor Interactions, Aalborg University, Aalborg, Denmark Introduction: Application of electrical stimulation through conventional surface electrodes activates both non-nociceptive and nociceptive fibers. To encompass this problem, electrical stimulation through small area pin electrode was introduced where subjective description of pain quality indicated preferential activation of nociceptors. The present study aimed to show that brain areas involved in nociceptive processing are activated by stimulation through cutaneous pin electrode (CPE) to a larger extent than conventional surface electrodes. Methods: Evoked potentials (EPs) were induced by electrical stimulation through conventional surface and CPE electrodes. The EPs were recorded from 62 scalp electrodes in 12 healthy volunteers where stimulation intensity was ten times the sensory threshold. Dipolar models of brain sources were built by using the brain electrical source analysis. Results: The solution for CPE was a 5 dipole model and had a bilateral distribution. The solution for the conventional large area surface electrode was a 4 dipole model and had a more lateralised solution. The dipolar model for the CPE was very similar to that previously described to explain the topography of laser EPs. Since laser stimuli mainly activate nociceptive fibres, the strong similarity suggests that only nociceptive inputs are involved in generation of CPE evoked responses. Conclusion: The current study gives evidence that CPE activates the nociceptive brain areas to a greater extent than conventional surface electrode. Therefore, CPEs should preferentially be utilized in future studies where electrical stimuli are used to study nociception. Disclosure: None declared
T117 THE ROLE OF SPINAL GLUTAMATE UPTAKE VIA GLUTAMATE TRANSPORTER FOR INCISION-INDUCED PAIN BEHAVIORS IN RATS S. Reichl1 *, A. Boecker1 , V. Keller1 , P.K. Zahn2 , E.M. Pogatzki-Zahn1 . 1 Department of Anaesthesiology and Intensive Care, University Hospital Muenster, Muenster, 2 Ruhr-University Bochum, BG-Kliniken Bergmannsheil, Bochum, Germany Background: The glial glutamate-transporter GLAST and GLT-1 regulate extracellular concentration of glutamate and may contribute to pain after incision. We assessed the role of mitogenactivated protein kinase (MAPK) for spinal expression of GLAST and GLT-1 and pain behavior after surgical incision. Methods: Rats with intrathecal (IT) catheter (n = 122) underwent plantar incision. All rats received SB203580 (MAPK p38inhibtor; 2 mg; saline; n = 30), PD98059 (MAPK ERK-inhibitor; 2 mg; 10%DMSO; n = 33) or vehicle (n = 59) twice a day for 4 days. In these rats, mechanical withdrawal thresholds (WT, calibrated von Frey filaments), thermal withdrawal latencies (WL, Hargreaves Box) and non-evoked pain scores were re-evaluated every day, In 18 rats, expression pattern of GLAST and GLT-1 was investigated by immunohistochemistry after incision and drug administration and in 31 rats, extracellular recordings of dorsal horn neurons were performed. Results: SB203580 but not PD98059 significantly enhanced the spontaneous pain at rest after incision. WT and WL were not increased in SB203580 or PD98059 treated rats. Similar, SB203580
20
POSTER SESSIONS / European Journal of Pain Supplements 5 (2011) 15–295
but not PD98059 inhibited the upregulation of GLAST and GLT-1 in the lumbal spinal cord after incision. Spontaneous activity of deep HT-neurons but not WDR-neurons was increased in rats treated with SB203580 after incision. Conclusions: Upregulation of GLAST and GLT-1 expression after incision is modulated by activation of p38 but not by ERK; this upregulation occurs in HT neurons which are presumably responsible for non-evoked pain after incision. Thus, the blockade of this process leads to prolonged non-evoked pain behavior due to increased spontaneous activity via increased glutamate uptake in HT neurons. Disclosure: None declared
T118 THE ANTIHYPERALGESIC EFFECT OF TAPENTADOL IN DIABETIC NEUROPATHIC MICE RESULTS FROM A SYNERGISTIC INTERACTION OF SPINAL AND SUPRASPINAL MECHANISMS T. Christoph1 *, J. De Vry1 , T. Hertrampf2 , T. Tzschentke1 . 1 Global Preclinical Research and Development, Department of Pharmacology, 2 Department of Molecular Pharmacology, Gr¨ unenthal GmbH, Aachen, Germany Background and Aims: Tapentadol is a m-opioid receptor (MOR) agonist and norepinephrine reuptake inhibitor, with high efficacy in neuropathic pain models and intrinsic synergistic interaction of both mechanisms. Although it is likely that the spinal cord is an important site for this intrinsic synergy, this hypothesis has not been experimentally verified. Methods: Diabetes was induced in mice by single administration of streptozotocin. Diabetic and weight-matched non-diabetic control mice were tested for the occurrence of nocifensive reactions on a 50°C hot plate. Spinal (i.t.) and supraspinal (i.c.v.) administration of drug and/or vehicle was performed under brief ether anesthesia and nocifensive reactions were tested before and 15, 30, 45 and 60 min after drug administration. Results: In diabetic mice, tapentadol (0.1–3.16 mg/animal) showed full efficacy after i.t. as well as i.c.v. administration (ED50 : 0.42 i.t., 0.18 i.c.v.). Combined administration of equi-analgesic doses revealed spinal-supraspinal synergy (ED50 : 0.053 i.t.+i.c.v.). Likewise, morphine (0.001–10 mg/animal) showed efficacy after both routes of administration (ED50 : 0.547 i.t., 0.004 i.c.v.) and a synergistic interaction after combined spinal/supraspinal administration (ED50 : 0.014 i.t.+i.c.v.). Conclusions: Results demonstrate that tapentadol is a centrally acting analgesic with high potency after i.c.v. and i.t. administration. The 50-fold potency difference between morphine and tapentadol after supraspinal administration is similar to the difference between both molecules in affinity for the MOR. In contrast, spinal potencies of both drugs did not differ, corresponding to similar potencies after systemic administration, suggesting that spinal mechanisms play a crucial role for the intrinsic synergy of tapentadol. Disclosure: All authors are paid employees of Grunenthal ¨ GmbH, manufacturer of tapentadol.
T119 HYPERALGESIA TO SUPERFICIAL AND DEEP MECHANICAL STIMULATION WITHIN AND OUTSIDE A UVB IRRADIATED AREA S. Lo Vecchio *, T. Graven-Nielsen, S. Finocchietti, P. Gazerani, L. Arendt-Nielsen. Health Science and Technology, Aalborg Universita, Aalborg, Denmark Background and Aims: Ultraviolet B (UVB) inflammatory pain model is often used to induce a stable hyperalgesic area in human skin. The aim of the present study was to evaluate whether this model induces a state of mechanical hyperalgesia in both superficial and deep-tissue within and outside of the irradiated area. Methods: An area of 3 × 4 cm, located on mid volar forearms of 12 healthy males, was irradiated by UVB (Medlight, Germany; 3×MED: Minimal Erythema Dose). Applying quantitative sensory
assessments, mechanical pain threshold changes were detected one day after irradiation, within and outside of the irradiated area. Sensitivity to cutaneous mechanical stimuli was assessed using von Frey hairs (Somedic, Sweden) and deep-tissue pressure pain thresholds were evaluated on 12 spots (4 within and 8 outside, distant 1.5 cm from the irradiated area) by a computer-controlled pressure algometer (Aalborg University, Denmark; 1.0 cm2 flat probe). Possible relation between applied pressure intensity and pain scores on a visual analogue scale (VAS) was also evaluated. Results: Cutaneous mechanical pain thresholds were significantly decreased within and outside the irradiated area (P < 0.05). Deeptissue pressure pain thresholds also showed a widespread and significant decrease (P < 0.001). The pressure-VAS curve highlighted a left-shift both within and outside the irradiated area (P < 0.05) with a remarkable change within the area. Conclusions: Cutaneous UVB irradiation reduced superficial and deep mechanical pain thresholds illustrating the existence of both primary and secondary hyperalgesia to mechanical stimuli. Disclosure: None declared
T120 MATERNAL SEPARATION DELAYS THE FUNCTIONAL ESTABLISHMENT OF ASCENDING AND DESCENDING NOCICEPTIVE CIRCUITS IN THE RAT SPINAL CORD 1 P.-E. Juif1,2 *, N. Petit Demouliere1 , A. Lacaud1 , V. Lelievre ` , P. Darbon1 , P. Poisbeau1 . 1 Nociception & Pain, Institute of Cellular and Integrative Neurosciences, Strasbourg, France; 2 Neuropsychology, University of Luxembourg, Luxembourg, Luxembourg Background and Aims: At birth, the development of spinal nociceptive circuits is not yet achieved in rodents. Until postnatal day 14 (P14), C-fiber inputs are relatively sparse, produce weak excitation and does not contribute to wind up. Moreover, descending inhibitory pathways and among them diffuse noxious inhibitory controls (DNIC) become fully efficient at P21. Maternal separation (MS) in rats has already been shown to be associated with pain hypersensitivity at more adult stages. The goal of this study was to characterize in detail the effect of postnatal stress on the early establishment of functional C-fiber-mediated transmission and DNIC in spinal cord neurons. Methods: We used in vivo electrophysiological recordings of dorsal horn neurons in rats and behavioral tests to characterize the functional consequence of MS on nociception. Results: A fully fonctional C-fiber-mediated neurotransmission was strongly delayed after MS. Until P24, induction of DNIC in stressed rats was impossible and was even producing an excitation. DNIC was eventually recovered at a later stage suggesting that MS delays the efficacy of DNIC. Conclusions: In summary, we show that MS has major consequences on the establishment of a functional nociceptive spinal network. The underlying molecular mechanisms are currently under investigation. This study might have important implication in human studies while considering pain strategies in preterm neonates. Acknowledgments: This project is supported by the CNRS (France), the FNR (Luxembourg) and cofunded under the Marie Curie Actions of the European Commission (FP7-COFUND). Disclosure: None declared
T121 THE SPATIAL RESOLUTION OF THE NOCICEPTIVE SYSTEM: A PSYCHOPHYSICAL STUDY I. Weissman-Fogel1 *, N. Zwi2 , R. Defrin2 . 1 Department of Physical Therapy, Faculty of Social Welfare & Health Sciences, University of Haifa, Haifa, 2 Department of Physical Therapy, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel Background and Aims: Results regarding the spatial resolution of the pain system are contradictory. While microneurographic