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Descending serotonergic facilitation mediated through rat spinal 5HT3 receptors is unaltered following carrageenan inflammation
Neuroscience Letters 361 (2004) 229–231 www.elsevier.com/locate/neulet
Descending serotonergic facilitation mediated through rat spinal 5HT3 receptors is unaltered following carrageenan inflammationq Wahida Rahman*, Rie Suzuki, Lars J. Rygh, Anthony H. Dickenson Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK
Abstract A descending facilitatory drive originating from superficial dorsal horn NK1-expressing neurones and relaying through parabrachial and rostroventral medial medulla to act on deep dorsal horn neurones, mediated through spinal 5HT3 receptors, was recently documented. To determine if this pathway plays a role in the pathophysiology of inflammation, we investigated the effects of spinally administered ondansetron (a selective 5HT3 receptor antagonist) on deep dorsal horn neuronal responses in carrageenan inflamed and naı¨ve animals using in vivo electrophysiology. The mechanical and thermal evoked responses of spinal neurones were dose dependently attenuated by ondansetron to a similar degree in both groups. In contrast, the electrically evoked responses (Ab-, Ad-, C-fibre evoked response and postdischarge) remained unaltered in both groups. Thus 5HT3 receptor mediated descending facilitation remains unaltered at this stage after tissue injury. q 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Serotonin; Tonic descending facilitation; Inflammation; Rat
Damage to peripheral tissues typically results in the development of peripheral and central sensitization and clinically manifests as hyperalgesia and mechanical allodynia. Recent evidence has highlighted the importance of facilitatory pathways arising from the brainstem that may contribute to the development of central sensitization and result in an amplification of pain response within the central nervous system [10,17]. We have recently demonstrated that one such excitatory influence is mediated through the action of serotonin (released from supraspinal origins) on spinal 5HT3 receptors exerting powerful pronociceptive effects on spinal transmission. This serotonergic circuit is necessary for the full coding of polymodal peripheral inputs by deep dorsal horn neurones [14], but what is not known is its capacity for change following persistent pain states. Carrageenan inflammation has been shown to produce significant plasticity in the spinal cord, and this is supported pharmacologically with numerous agents including opioids, cholecystokinin and N-methyl-D -aspartate receptor antagonists, etc. We investigated whether the 5HT3 receptorq This paper is dedicated to Professor Manfred Zimmermann as a tribute to his many contributions to the understanding of spinal mechanisms of nociception. * Corresponding author. Tel.: þ44-20-7679-3737; fax: þ 44-20-76793742. E-mail address: [email protected] (W. Rahman).
mediated descending pathway may be enhanced following peripheral tissue injury, and whether it could contribute to any central plasticity that accompanies this injury state. A total of 38 (n ¼ 17 naı¨ve, n ¼ 21 carrageenan) male rats (Sprague –Dawley, Central Biological Services, University College London, UK) were employed for this study. All experimental procedures were approved by the UK Home Office and follow the guidelines under the International Association for the Study of Pain [20]. Inflammation was induced by an intraplantar injection of 2% carrageenan (100 ml) into the ipsilateral hindpaw. Animals were anaesthetized with halothane (1.0 –1.2%, 66% N2O and 33% O2) and extracellular recordings were made from ipsilateral deep dorsal horn neurones (lamina V –VI) with defined receptive fields in the toe regions of the hindpaw [18]. A train of 16 transcutaneous electrical stimuli (2-ms wide pulses, 0.5 Hz) was applied at 3-times the threshold current for C-fibres and responses evoked by Ab- (0 – 20 ms), Ad- (20 –90 ms) and C-fibres (90 – 300 ms) were separated and quantified on the basis of latency. Responses occurring after the C-fibre latency band were taken to be the post-discharge of the cell (300 – 800 ms). The peripheral receptive field was also stimulated using a range of natural stimuli (von Frey filaments 1 – 75 g and heat 35 – 50 8C) over a period of 10 s. Data were captured and analysed by a CED 1401 interface coupled to a Pentium computer with Spike 2
0304-3940/03/$ - see front matter q 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2003.12.069
230
W. Rahman et al. / Neuroscience Letters 361 (2004) 229–231
Table 1 Electrically evoked responses of deep dorsal horn neurones
Naı¨ve (n ¼ 17) Carrageenan (n ¼ 21)
A-beta
A-delta
C-fibre (C-f)
Post-discharge
C-f threshold (mA)
99 ^ 7 117 ^ 10
52 ^ 9 80 ^ 11
357 ^ 30 390 ^ 29
135 ^ 26 149 ^ 14
1.6 ^ 0.2 1.5 ^ 0.4
Data are presented as mean ^ S.E.M. All the responses were comparable in the two groups.
software (Cambridge Electronic Design; PSTH and rate functions). Prior to drug administration, stable control responses to electrical and selected natural stimuli were established at 20-min intervals. Ondansetron (Zofran; Glaxo-Wellcome) was administered spinally (10, 50 and 100 mg/50 ml) and drug effects were followed over 1 h per dose at 20-min intervals. Analysis of variance (ANOVA) was used both to evaluate drug and group effects (groups (naı¨ve or carrageenan) and stimuli (heat or mechanical) as independent and neuronal response as dependent variables, one- and two-way ANOVA, respectively) on the natural stimuli. Otherwise Student’s t-test was used. Subcutaneous injections of carrageenan into the hindpaw resulted in an obvious inflammatory response as evidenced by swelling and redness of the entire paw shortly after the injection. Pre-drug characterization of 38 deep dorsal horn neurones revealed no significant differences between the naı¨ve and carrageenan treated animals with regards to the electrically evoked Ab-, Ad- and C-fibre-mediated response, post-discharge and the activation threshold for C-fibres (n ¼ 38, Table 1). The naturally evoked responses were also comparable in the two groups (Fig. 1, n ¼ 38). Following their physiological characterization, 21 deep dorsal horn neurones (10 and 11 in naı¨ve and carrageenan group, respectively) were randomly chosen for the subsequent pharmacological investigations. Spinally applied ondansetron (10, 50 and 100 mg/50 ml) showed a doserelated effect. This was evidenced as the lower dose was ineffective and the two highest doses produced a significant inhibition of both the heat and mechanical responses (P , 0; 01 for both the heat and mechanically evoked responses in both the naı¨ve and the carrageenan groups, oneway ANOVA, n ¼ 21) (data not shown). However, there were no significant differences between the naı¨ve and carrageenan groups with respect to the effect of ondansetron. Fig. 1 clearly illustrates the comparable inhibitory effects of the middle dose (50 mg) of ondansetron in naı¨ve animals and following carrageenan inflammation (P ¼ 0:79 and P ¼ 0:87 for mechanical and heat, respectively, twoway ANOVA, n ¼ 21). This dose (50 mg ondansetron) was previously shown to reduce neuronal responses following peripheral formalin injection [4]. In the present study, we characterized the electrically and naturally evoked responses of spinal neurones 3 h after induction of carrageenan inflammation, and furthermore investigated the effects of a clinically available 5HT3 receptor antagonist, ondansetron, on the evoked neuronal responses. Unlike neuropathy where significant plasticity is
observed in the spinal cord 2 weeks after nerve injury [2,3, 8], electrophysiological characterization of deep dorsal horn neurones revealed no marked alterations in their response characteristic following carrageenan inflammation. This is in keeping with previous data demonstrating comparable electrical evoked responses of carrageenan-inflamed rats compared to uninjected naı¨ve controls [7,11,12,15]. We extend these observations to show that neuronal responses evoked by innocuous and noxious mechanical punctate and thermal stimuli are similarly unaltered after carrageenan inflammation despite obvious signs of peripheral inflammation. Interestingly, despite the lack of obvious changes in the response characteristics of deep dorsal horn neurones, a number of pharmacological systems do undergo significant
Fig. 1. Fifty micrograms of ondansetron produced a significant inhibition of the mechanical and heat evoked responses in both animal groups (P , 0:01). The inhibitory effects of ondansetron were the same in the carrageenan and naı¨ve groups.
W. Rahman et al. / Neuroscience Letters 361 (2004) 229–231
plasticity following carrageenan inflammation in the spinal cord, and furthermore animals display marked mechanical allodynia and thermal hyperalgesia [5,11,13,16]. It may be that there are differential changes in threshold responses that underlie behavioural hyperalgesia as compared to suprathreshold neuronal responses. Furthermore, it is possible that the behavioural changes seen after carrageenan are masked by the presence of anaesthesia but equally, the former could include facilitations of motor pathways. For example, there are differences between dorsal horn neuronal wind-up and that seen in motor systems [19] that indicate that the sensory/discriminative signals sent by dorsal horn neurones may be very different from the motor unit activity. There is mounting evidence for descending pathways originating from the midbrain and brainstem that can modulate sensory transmission either by exerting inhibitory or excitatory influences onto the spinal cord [9,17]. These tonic descending influences were proposed to be dependent on the modality of the test stimulus, the type of injury and on the segmental level of the reflex [6]. The overall balance of these descending influences, together with intrinsic spinal mechanisms and peripheral inputs would ultimately determine the level of excitability within the spinal cord, and possibly influence the behavioural outcome of the animal. More recently, it was proposed that an overdrive or inappropriate activation of these descending excitatory pathways may be one mechanism that underlies abnormal pain behaviour associated with persistent pain states [10]. One such excitatory pathway known to facilitate nociception in the spinal cord is mediated through the action of 5HT – originating from the rostro-ventromedial medulla – on spinal 5HT3 receptors [1,4,14]. Our present finding of a selective and dose-related attenuation of the naturally evoked responses (but not electrically evoked responses) seen after ondansetron administration in naı¨ve and carrageenan-injected animals provides further evidence for a serotonergic facilitatory influence on these neuronal measures. Since the actions of the drug did not differ between naı¨ve and carrageenan-inflamed animals, this descending excitatory pathway is unlikely to undergo plasticity 3 h after tissue injury, and hence suggests that hyperalgesia and allodynia manifested after tissue injury involves different peripheral and/or central mechanisms.
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9] [10] [11]
[12]
[13]
[14]
[15]
[16]
Acknowledgements This work is funded by the Wellcome Trust, the London Pain Consortium and the Norwegian Research Council.
[17] [18]
[19]
References [20] [1] Z. Ali, G. Wu, A. Kozlov, S. Barasi, The role of 5HT3 in nociceptive
231
processing in the rat spinal cord: results from behavioural and electrophysiological studies, Neurosci. Lett. 208 (1996) 203–207. V. Chapman, R. Suzuki, A.H. Dickenson, Electrophysiological characterization of spinal neuronal response properties in anaesthetized rats after ligation of spinal nerves L5–L6, J. Physiol. 507 (1998) 881– 894. M. Cumberbatch, E. Carlson, A. Wyatt, S. Boyce, R. Hill, N. Rupniak, Reversal of behavioural and electrophysiological correlates of experimental peripheral neuropathy by the NK1 receptor antagonist GR205171 in rats, Neuropharmacology 37 (1998) 1535–1543. G.M. Green, J. Scarth, A. Dickenson, An excitatory role for 5-HT in spinal inflammatory nociceptive transmission; state-dependent actions via dorsal horn 5-HT(3) receptors in the anaesthetized rat, Pain 89 (2000) 81– 88. G. Hedo, J.M. Laird, J.A. Lopez-Garcia, Time-course of spinal sensitization following carrageenan-induced inflammation in the young rat: a comparative electrophysiological and behavioural study in vitro and in vivo, Neuroscience 92 (1999) 309–318. T. Kauppila, V.K. Kontinen, A. Pertovaara, Influence of spinalization on spinal withdrawal reflex responses varies depending on the submodality of the test stimulus and the experimental pathophysiological condition in the rat, Brain Res. 797 (1998) 234–242. S. Kelly, V. Chapman, Spinal administration of capsazepine inhibits noxious evoked responses of dorsal horn neurons in non-inflamed and carrageenan inflamed rats, Brain Res. 935 (2002) 103–108. J.M. Laird, G.J. Bennett, An electrophysiological study of dorsal horn neurons in the spinal cord of rats with an experimental peripheral neuropathy, J. Neurophysiol. 69 (1993) 2072– 2085. M. Millan, Descending control of pain, Prog. Neurobiol. 66 (2002) 354–474. F. Porreca, M.H. Ossipov, G.F. Gebhart, Chronic pain and medullary descending facilitation, Trends Neurosci 25 (2002) 319–325. L. Rygh, F. Svendsen, K. Hole, A. Tjolsen, Increased spinal Nmethyl-D-aspartate receptor function after 20 h of carrageenaninduced inflammation, Pain 93 (2001) 15–21. L.C. Stanfa, V.K. Kontinen, A.H. Dickenson, Effects of spinally administered P2X receptor agonists and antagonists on the responses of dorsal horn neurones recorded in normal, carrageenan-inflamed and neuropathic rats, Br. J. Pharmacol. 129 (2000) 351–359. L.C. Stanfa, A.F. Sullivan, A.H. Dickenson, Alterations in neuronal excitability and the potency of spinal mu, delta and kappa opioids after carrageenan-induced inflammation, Pain 50 (1992) 345 –354. R. Suzuki, S. Morcuende, M. Webber, S. Hunt, A. Dickenson, Superficial NK1 expressing neurones control spinal excitability by activation of descending pathways, Nat. Neurosci. 5 (2002) 1319– 1326. R. Suzuki, L. Stanfa, E. Kowaluk, M. Williams, M. Jarvis, A. Dickenson, The effect of ABT-702, a novel adenosine kinase inhibitor, on the responses of spinal neurones following carrageenan inflammation and peripheral nerve injury, Br. J. Pharmacol. 132 (2001) 1615– 1623. F. Svendsen, L. Rygh, K. Hole, A. Tjolsen, Dorsal horn NMDA receptor function is changed after peripheral inflammation, Pain (1999) 83. M.O. Urban, G.F. Gebhart, Supraspinal contributions to hyperalgesia, Proc. Natl. Acad. Sci. USA 96 (1999) 7687–7692. C.E. Urch, A.H. Dickenson, In vivo single unit extracellular recordings from spinal cord neurones of rats, Brain Res. Brain Res. Protocols 12 (2003) 26–34. H.J. You, C. Dahl Morch, J. Chen, L. Arendt-Nielsen, Simultaneous recordings of wind-up of paired spinal dorsal horn nociceptive neuron and nociceptive flexion reflex in rats, Brain Res. 960 (2003) 235–245. M. Zimmermann, Ethical guidelines for investigations of experimental pain in conscious animals, Pain 16 (1983) 109– 110.
Descending serotonergic facilitation mediated through rat spinal 5HT3 receptors is unaltered following carrageenan inflammationq Wahida Rahman*, Rie Suzuki, Lars J. Rygh, Anthony H. Dickenson Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK
Abstract A descending facilitatory drive originating from superficial dorsal horn NK1-expressing neurones and relaying through parabrachial and rostroventral medial medulla to act on deep dorsal horn neurones, mediated through spinal 5HT3 receptors, was recently documented. To determine if this pathway plays a role in the pathophysiology of inflammation, we investigated the effects of spinally administered ondansetron (a selective 5HT3 receptor antagonist) on deep dorsal horn neuronal responses in carrageenan inflamed and naı¨ve animals using in vivo electrophysiology. The mechanical and thermal evoked responses of spinal neurones were dose dependently attenuated by ondansetron to a similar degree in both groups. In contrast, the electrically evoked responses (Ab-, Ad-, C-fibre evoked response and postdischarge) remained unaltered in both groups. Thus 5HT3 receptor mediated descending facilitation remains unaltered at this stage after tissue injury. q 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Serotonin; Tonic descending facilitation; Inflammation; Rat
Damage to peripheral tissues typically results in the development of peripheral and central sensitization and clinically manifests as hyperalgesia and mechanical allodynia. Recent evidence has highlighted the importance of facilitatory pathways arising from the brainstem that may contribute to the development of central sensitization and result in an amplification of pain response within the central nervous system [10,17]. We have recently demonstrated that one such excitatory influence is mediated through the action of serotonin (released from supraspinal origins) on spinal 5HT3 receptors exerting powerful pronociceptive effects on spinal transmission. This serotonergic circuit is necessary for the full coding of polymodal peripheral inputs by deep dorsal horn neurones [14], but what is not known is its capacity for change following persistent pain states. Carrageenan inflammation has been shown to produce significant plasticity in the spinal cord, and this is supported pharmacologically with numerous agents including opioids, cholecystokinin and N-methyl-D -aspartate receptor antagonists, etc. We investigated whether the 5HT3 receptorq This paper is dedicated to Professor Manfred Zimmermann as a tribute to his many contributions to the understanding of spinal mechanisms of nociception. * Corresponding author. Tel.: þ44-20-7679-3737; fax: þ 44-20-76793742. E-mail address: [email protected] (W. Rahman).
mediated descending pathway may be enhanced following peripheral tissue injury, and whether it could contribute to any central plasticity that accompanies this injury state. A total of 38 (n ¼ 17 naı¨ve, n ¼ 21 carrageenan) male rats (Sprague –Dawley, Central Biological Services, University College London, UK) were employed for this study. All experimental procedures were approved by the UK Home Office and follow the guidelines under the International Association for the Study of Pain [20]. Inflammation was induced by an intraplantar injection of 2% carrageenan (100 ml) into the ipsilateral hindpaw. Animals were anaesthetized with halothane (1.0 –1.2%, 66% N2O and 33% O2) and extracellular recordings were made from ipsilateral deep dorsal horn neurones (lamina V –VI) with defined receptive fields in the toe regions of the hindpaw [18]. A train of 16 transcutaneous electrical stimuli (2-ms wide pulses, 0.5 Hz) was applied at 3-times the threshold current for C-fibres and responses evoked by Ab- (0 – 20 ms), Ad- (20 –90 ms) and C-fibres (90 – 300 ms) were separated and quantified on the basis of latency. Responses occurring after the C-fibre latency band were taken to be the post-discharge of the cell (300 – 800 ms). The peripheral receptive field was also stimulated using a range of natural stimuli (von Frey filaments 1 – 75 g and heat 35 – 50 8C) over a period of 10 s. Data were captured and analysed by a CED 1401 interface coupled to a Pentium computer with Spike 2
0304-3940/03/$ - see front matter q 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2003.12.069
230
W. Rahman et al. / Neuroscience Letters 361 (2004) 229–231
Table 1 Electrically evoked responses of deep dorsal horn neurones
Naı¨ve (n ¼ 17) Carrageenan (n ¼ 21)
A-beta
A-delta
C-fibre (C-f)
Post-discharge
C-f threshold (mA)
99 ^ 7 117 ^ 10
52 ^ 9 80 ^ 11
357 ^ 30 390 ^ 29
135 ^ 26 149 ^ 14
1.6 ^ 0.2 1.5 ^ 0.4
Data are presented as mean ^ S.E.M. All the responses were comparable in the two groups.
software (Cambridge Electronic Design; PSTH and rate functions). Prior to drug administration, stable control responses to electrical and selected natural stimuli were established at 20-min intervals. Ondansetron (Zofran; Glaxo-Wellcome) was administered spinally (10, 50 and 100 mg/50 ml) and drug effects were followed over 1 h per dose at 20-min intervals. Analysis of variance (ANOVA) was used both to evaluate drug and group effects (groups (naı¨ve or carrageenan) and stimuli (heat or mechanical) as independent and neuronal response as dependent variables, one- and two-way ANOVA, respectively) on the natural stimuli. Otherwise Student’s t-test was used. Subcutaneous injections of carrageenan into the hindpaw resulted in an obvious inflammatory response as evidenced by swelling and redness of the entire paw shortly after the injection. Pre-drug characterization of 38 deep dorsal horn neurones revealed no significant differences between the naı¨ve and carrageenan treated animals with regards to the electrically evoked Ab-, Ad- and C-fibre-mediated response, post-discharge and the activation threshold for C-fibres (n ¼ 38, Table 1). The naturally evoked responses were also comparable in the two groups (Fig. 1, n ¼ 38). Following their physiological characterization, 21 deep dorsal horn neurones (10 and 11 in naı¨ve and carrageenan group, respectively) were randomly chosen for the subsequent pharmacological investigations. Spinally applied ondansetron (10, 50 and 100 mg/50 ml) showed a doserelated effect. This was evidenced as the lower dose was ineffective and the two highest doses produced a significant inhibition of both the heat and mechanical responses (P , 0; 01 for both the heat and mechanically evoked responses in both the naı¨ve and the carrageenan groups, oneway ANOVA, n ¼ 21) (data not shown). However, there were no significant differences between the naı¨ve and carrageenan groups with respect to the effect of ondansetron. Fig. 1 clearly illustrates the comparable inhibitory effects of the middle dose (50 mg) of ondansetron in naı¨ve animals and following carrageenan inflammation (P ¼ 0:79 and P ¼ 0:87 for mechanical and heat, respectively, twoway ANOVA, n ¼ 21). This dose (50 mg ondansetron) was previously shown to reduce neuronal responses following peripheral formalin injection [4]. In the present study, we characterized the electrically and naturally evoked responses of spinal neurones 3 h after induction of carrageenan inflammation, and furthermore investigated the effects of a clinically available 5HT3 receptor antagonist, ondansetron, on the evoked neuronal responses. Unlike neuropathy where significant plasticity is
observed in the spinal cord 2 weeks after nerve injury [2,3, 8], electrophysiological characterization of deep dorsal horn neurones revealed no marked alterations in their response characteristic following carrageenan inflammation. This is in keeping with previous data demonstrating comparable electrical evoked responses of carrageenan-inflamed rats compared to uninjected naı¨ve controls [7,11,12,15]. We extend these observations to show that neuronal responses evoked by innocuous and noxious mechanical punctate and thermal stimuli are similarly unaltered after carrageenan inflammation despite obvious signs of peripheral inflammation. Interestingly, despite the lack of obvious changes in the response characteristics of deep dorsal horn neurones, a number of pharmacological systems do undergo significant
Fig. 1. Fifty micrograms of ondansetron produced a significant inhibition of the mechanical and heat evoked responses in both animal groups (P , 0:01). The inhibitory effects of ondansetron were the same in the carrageenan and naı¨ve groups.
W. Rahman et al. / Neuroscience Letters 361 (2004) 229–231
plasticity following carrageenan inflammation in the spinal cord, and furthermore animals display marked mechanical allodynia and thermal hyperalgesia [5,11,13,16]. It may be that there are differential changes in threshold responses that underlie behavioural hyperalgesia as compared to suprathreshold neuronal responses. Furthermore, it is possible that the behavioural changes seen after carrageenan are masked by the presence of anaesthesia but equally, the former could include facilitations of motor pathways. For example, there are differences between dorsal horn neuronal wind-up and that seen in motor systems [19] that indicate that the sensory/discriminative signals sent by dorsal horn neurones may be very different from the motor unit activity. There is mounting evidence for descending pathways originating from the midbrain and brainstem that can modulate sensory transmission either by exerting inhibitory or excitatory influences onto the spinal cord [9,17]. These tonic descending influences were proposed to be dependent on the modality of the test stimulus, the type of injury and on the segmental level of the reflex [6]. The overall balance of these descending influences, together with intrinsic spinal mechanisms and peripheral inputs would ultimately determine the level of excitability within the spinal cord, and possibly influence the behavioural outcome of the animal. More recently, it was proposed that an overdrive or inappropriate activation of these descending excitatory pathways may be one mechanism that underlies abnormal pain behaviour associated with persistent pain states [10]. One such excitatory pathway known to facilitate nociception in the spinal cord is mediated through the action of 5HT – originating from the rostro-ventromedial medulla – on spinal 5HT3 receptors [1,4,14]. Our present finding of a selective and dose-related attenuation of the naturally evoked responses (but not electrically evoked responses) seen after ondansetron administration in naı¨ve and carrageenan-injected animals provides further evidence for a serotonergic facilitatory influence on these neuronal measures. Since the actions of the drug did not differ between naı¨ve and carrageenan-inflamed animals, this descending excitatory pathway is unlikely to undergo plasticity 3 h after tissue injury, and hence suggests that hyperalgesia and allodynia manifested after tissue injury involves different peripheral and/or central mechanisms.
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9] [10] [11]
[12]
[13]
[14]
[15]
[16]
Acknowledgements This work is funded by the Wellcome Trust, the London Pain Consortium and the Norwegian Research Council.
[17] [18]
[19]
References [20] [1] Z. Ali, G. Wu, A. Kozlov, S. Barasi, The role of 5HT3 in nociceptive
231
processing in the rat spinal cord: results from behavioural and electrophysiological studies, Neurosci. Lett. 208 (1996) 203–207. V. Chapman, R. Suzuki, A.H. Dickenson, Electrophysiological characterization of spinal neuronal response properties in anaesthetized rats after ligation of spinal nerves L5–L6, J. Physiol. 507 (1998) 881– 894. M. Cumberbatch, E. Carlson, A. Wyatt, S. Boyce, R. Hill, N. Rupniak, Reversal of behavioural and electrophysiological correlates of experimental peripheral neuropathy by the NK1 receptor antagonist GR205171 in rats, Neuropharmacology 37 (1998) 1535–1543. G.M. Green, J. Scarth, A. Dickenson, An excitatory role for 5-HT in spinal inflammatory nociceptive transmission; state-dependent actions via dorsal horn 5-HT(3) receptors in the anaesthetized rat, Pain 89 (2000) 81– 88. G. Hedo, J.M. Laird, J.A. Lopez-Garcia, Time-course of spinal sensitization following carrageenan-induced inflammation in the young rat: a comparative electrophysiological and behavioural study in vitro and in vivo, Neuroscience 92 (1999) 309–318. T. Kauppila, V.K. Kontinen, A. Pertovaara, Influence of spinalization on spinal withdrawal reflex responses varies depending on the submodality of the test stimulus and the experimental pathophysiological condition in the rat, Brain Res. 797 (1998) 234–242. S. Kelly, V. Chapman, Spinal administration of capsazepine inhibits noxious evoked responses of dorsal horn neurons in non-inflamed and carrageenan inflamed rats, Brain Res. 935 (2002) 103–108. J.M. Laird, G.J. Bennett, An electrophysiological study of dorsal horn neurons in the spinal cord of rats with an experimental peripheral neuropathy, J. Neurophysiol. 69 (1993) 2072– 2085. M. Millan, Descending control of pain, Prog. Neurobiol. 66 (2002) 354–474. F. Porreca, M.H. Ossipov, G.F. Gebhart, Chronic pain and medullary descending facilitation, Trends Neurosci 25 (2002) 319–325. L. Rygh, F. Svendsen, K. Hole, A. Tjolsen, Increased spinal Nmethyl-D-aspartate receptor function after 20 h of carrageenaninduced inflammation, Pain 93 (2001) 15–21. L.C. Stanfa, V.K. Kontinen, A.H. Dickenson, Effects of spinally administered P2X receptor agonists and antagonists on the responses of dorsal horn neurones recorded in normal, carrageenan-inflamed and neuropathic rats, Br. J. Pharmacol. 129 (2000) 351–359. L.C. Stanfa, A.F. Sullivan, A.H. Dickenson, Alterations in neuronal excitability and the potency of spinal mu, delta and kappa opioids after carrageenan-induced inflammation, Pain 50 (1992) 345 –354. R. Suzuki, S. Morcuende, M. Webber, S. Hunt, A. Dickenson, Superficial NK1 expressing neurones control spinal excitability by activation of descending pathways, Nat. Neurosci. 5 (2002) 1319– 1326. R. Suzuki, L. Stanfa, E. Kowaluk, M. Williams, M. Jarvis, A. Dickenson, The effect of ABT-702, a novel adenosine kinase inhibitor, on the responses of spinal neurones following carrageenan inflammation and peripheral nerve injury, Br. J. Pharmacol. 132 (2001) 1615– 1623. F. Svendsen, L. Rygh, K. Hole, A. Tjolsen, Dorsal horn NMDA receptor function is changed after peripheral inflammation, Pain (1999) 83. M.O. Urban, G.F. Gebhart, Supraspinal contributions to hyperalgesia, Proc. Natl. Acad. Sci. USA 96 (1999) 7687–7692. C.E. Urch, A.H. Dickenson, In vivo single unit extracellular recordings from spinal cord neurones of rats, Brain Res. Brain Res. Protocols 12 (2003) 26–34. H.J. You, C. Dahl Morch, J. Chen, L. Arendt-Nielsen, Simultaneous recordings of wind-up of paired spinal dorsal horn nociceptive neuron and nociceptive flexion reflex in rats, Brain Res. 960 (2003) 235–245. M. Zimmermann, Ethical guidelines for investigations of experimental pain in conscious animals, Pain 16 (1983) 109– 110.