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Exercise induces hypoalgesia through conditioned pain modulation
Abstracts (244) Peroxynitrite decomposition catalyst blocks paclitaxelinduced neuropathic pain: microarray analysis of spinal cord gene expression T Doyle, Z Chen, and D Salvemini; St. Louis University, St. Louis, MO
The Journal of Pain
P37
E10 Endogenous Pain Modulation (246) Exercise induces hypoalgesia through conditioned pain modulation
Chemotherapy-induced neuropathic pain (CIPN) develops in a majority of patients receiving paclitaxel, reducing the clinical effectiveness of this important class of anticancer drugs. Paclitaxel administration induces peripheral mitochondrial dysfunction and neuropathy resulting in the development of central sensitization and CIPN. The mechanisms through which this central sensitization develops are poorly understood. Our lab has established a role for peroxynitrite in the central sensitization from several pain etiologies, however, its role in the development of CIPN is not known. Through microarray analysis of spinal cord gene expression, we ventured to identify potential nitroxidativesensitive mechanisms through which the development of CIPN occurs. Administration of paclitaxel (cumulative dose of 4 mg/kg on 4 alternate days) induced mechanical hyperalgesia in rats that was >90% attenuated with the co-administration (10 mg/kg/16d, s.c.) of the peroxynitrite decomposition catalyst, (PNDC, MnTE-2-PyP5+). Paclitaxel-induced mechanical hyperalgesia was accompanied at 16 days by peroxynitrite-mediated increased expression of genes associated with antigen presentation and immune activation; events that were prevented in rats co-treated with PNDC. These data provide evidence for a novel therapeutic target for treating paclitaxel-induced central sensitization and initial insight into potential peroxynitrite-mediated mechanisms involved in central sensitization in the development of CIPN. Supported by: NIH/NIDA (R01 DA024074, R21 DA023056).
L Ellingson and D Cook; University of Wisconsin, Madison, WI
(245) Mitochondrial Ca2+ uptake is essential for synaptic plasticity in pain
(247) Age-related changes in sensitivity to nociceptive stimuli and expression of spinal cord NR1 in Fisher 344 rats
H Kim, K Lee, J Wang, L Cui, S Kim, J Chung, and K Chung; Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX
M Jenschke, A Ratka, E Flores, M Singh, N Sumien, and M Forster; University of North Texas Health Science Center, Fort Worth, TX
The increase of cytosolic free-Ca2+ ([Ca2+]C) due to NMDA receptor activation is a key step for spinal cord synaptic plasticity by altering cellular signal transduction pathways. We focus on this plasticity as a cause of persistent pain. To provide a mechanism for these classic findings, we report that cytosolic free-Ca2+ do not trigger synaptic plasticity directly but must first enter into mitochondria. In particular we show that interfering with mitochondrial Ca2+ uptake during a cytosolic free-Ca2+ increase blocks induction of behavioral hyperalgesia and accompanying downstream cell signaling, with reduction of spinal long term potentiation (LTP). We further show that reducing the accompanying mitochondrial superoxide levels lessens hyperalgesia and LTP induction. These results indicate that [Ca2+]C requires downstream mitochondrial Ca2+ uptake with consequent production of superoxide for synaptic plasticity underlying certain types of chronic pain. These results suggest modifying mitochondrial Ca2+ uptake and/or superoxide levels as a type of chronic pain therapy that should also have broader biologic significance. This study was supported by NIH grants R01 NS031680 and P01 NS11255 and by the Korea Science and Engineering Foundation funded by the Ministry of Education, Science and Technology (No. 2009-0080939 and WCU program R32-10142).
Results from our studies indicate that aged rats exhibited greater sensitivity to punctate mechanical nociceptive stimulation than young rats. The present studies were designed to further explore the mechanism underlying the age-related increase in sensitivity and sensitization to punctate mechanical nociceptive stimulation and determine the involvement of NR1 in these effects. Activation of the NMDA receptor is integral to the initiation and maintenance of central sensitization whereby nociceptive activity is enhanced. We hypothesized that spinal cord NR1 expression will increase in response to punctate mechanical nociceptive stimulation and that age-related differences in magnitude of NR1 expression will be evident. Young and aged male Fischer 344 rats were exposed to von Frey filaments (0.07g – 26g) applied sequentially to primary, secondary, and tertiary regions of dorsal skin as determined in previous studies. Cutaneous trunci muscle reflex (CTMR) to von Frey filament stimulation was recorded and Western blot analysis was used to measure expression of NR1 in spinal cord. The results showed that aged rats had significantly greater responses to punctate mechanical nociceptive stimulation than young rats; this age difference was more pronounced at higher filament forces. Punctate mechanical nociceptive stimulation increased spinal NR1 expression but this increase was statistically significant only in young rats. In aged rats, a statistically significant decrease in NR1 expression negatively correlated with the increased response to punctuate nociceptive stimulation. These results imply that age-related changes in sensitivity to mechanical nociceptive stimuli may be evoked by a mechanism involving the NMDA system. Supported by NIH T32AG020494.
Research consistently shows that healthy women experience a decrease in sensitivity to experimental pain stimuli during and following exercise. The mechanisms that underlie this exercise-induced hypoalgesia (EIH) are unknown. EIH reliably occurs at higher intensities and longer durations of exercise, levels that are often painful. Thus, it has been suggested that EIH results from an endogenous pain inhibitory mechanism termed conditioned pain modulation (CPM), similar to diffuse noxious inhibitory controls. The purpose of this study was to determine whether exercise-induced muscle pain serves as a CPM stimulus, testing one potential mechanism of EIH. Sixteen healthy women (mean age 30 yrs) completed pain testing during three counter-balanced sessions separated by one week: (1) 10 minutes of painful exercise on a cycle ergometer, (2) 10 minutes of non-painful exercise and (3) 10 minutes of quiet rest. All sessions included a 10-minute recovery period. Intensity and unpleasantness ratings in response to noxious thermal stimuli applied to the palm were assessed at baseline, at minutes 5, 7, and 9 of the experimental session and at minutes 5 and 10 of recovery. Data were analyzed with two linear mixed effects ANCOVAs with session and time serving as independent variables, pain intensity and unpleasantness as dependent variables and systolic blood pressure as the covariate of interest. Results showed a significant (p< 0.01) session by time interaction for both pain intensity and pain unpleasantness demonstrating that pain sensitivity decreased more quickly and to a greater extent during painful exercise than during either non-painful exercise or quiet rest. Moreover, sensitivity remained lower during recovery from painful exercise than the other sessions. These results suggest that naturally occurring leg muscle pain induced by exercise may contribute to EIH through CPM. Supported by a grant from the University of Wisconsin Virginia Horne Henry Fund.
The Journal of Pain
P37
E10 Endogenous Pain Modulation (246) Exercise induces hypoalgesia through conditioned pain modulation
Chemotherapy-induced neuropathic pain (CIPN) develops in a majority of patients receiving paclitaxel, reducing the clinical effectiveness of this important class of anticancer drugs. Paclitaxel administration induces peripheral mitochondrial dysfunction and neuropathy resulting in the development of central sensitization and CIPN. The mechanisms through which this central sensitization develops are poorly understood. Our lab has established a role for peroxynitrite in the central sensitization from several pain etiologies, however, its role in the development of CIPN is not known. Through microarray analysis of spinal cord gene expression, we ventured to identify potential nitroxidativesensitive mechanisms through which the development of CIPN occurs. Administration of paclitaxel (cumulative dose of 4 mg/kg on 4 alternate days) induced mechanical hyperalgesia in rats that was >90% attenuated with the co-administration (10 mg/kg/16d, s.c.) of the peroxynitrite decomposition catalyst, (PNDC, MnTE-2-PyP5+). Paclitaxel-induced mechanical hyperalgesia was accompanied at 16 days by peroxynitrite-mediated increased expression of genes associated with antigen presentation and immune activation; events that were prevented in rats co-treated with PNDC. These data provide evidence for a novel therapeutic target for treating paclitaxel-induced central sensitization and initial insight into potential peroxynitrite-mediated mechanisms involved in central sensitization in the development of CIPN. Supported by: NIH/NIDA (R01 DA024074, R21 DA023056).
L Ellingson and D Cook; University of Wisconsin, Madison, WI
(245) Mitochondrial Ca2+ uptake is essential for synaptic plasticity in pain
(247) Age-related changes in sensitivity to nociceptive stimuli and expression of spinal cord NR1 in Fisher 344 rats
H Kim, K Lee, J Wang, L Cui, S Kim, J Chung, and K Chung; Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX
M Jenschke, A Ratka, E Flores, M Singh, N Sumien, and M Forster; University of North Texas Health Science Center, Fort Worth, TX
The increase of cytosolic free-Ca2+ ([Ca2+]C) due to NMDA receptor activation is a key step for spinal cord synaptic plasticity by altering cellular signal transduction pathways. We focus on this plasticity as a cause of persistent pain. To provide a mechanism for these classic findings, we report that cytosolic free-Ca2+ do not trigger synaptic plasticity directly but must first enter into mitochondria. In particular we show that interfering with mitochondrial Ca2+ uptake during a cytosolic free-Ca2+ increase blocks induction of behavioral hyperalgesia and accompanying downstream cell signaling, with reduction of spinal long term potentiation (LTP). We further show that reducing the accompanying mitochondrial superoxide levels lessens hyperalgesia and LTP induction. These results indicate that [Ca2+]C requires downstream mitochondrial Ca2+ uptake with consequent production of superoxide for synaptic plasticity underlying certain types of chronic pain. These results suggest modifying mitochondrial Ca2+ uptake and/or superoxide levels as a type of chronic pain therapy that should also have broader biologic significance. This study was supported by NIH grants R01 NS031680 and P01 NS11255 and by the Korea Science and Engineering Foundation funded by the Ministry of Education, Science and Technology (No. 2009-0080939 and WCU program R32-10142).
Results from our studies indicate that aged rats exhibited greater sensitivity to punctate mechanical nociceptive stimulation than young rats. The present studies were designed to further explore the mechanism underlying the age-related increase in sensitivity and sensitization to punctate mechanical nociceptive stimulation and determine the involvement of NR1 in these effects. Activation of the NMDA receptor is integral to the initiation and maintenance of central sensitization whereby nociceptive activity is enhanced. We hypothesized that spinal cord NR1 expression will increase in response to punctate mechanical nociceptive stimulation and that age-related differences in magnitude of NR1 expression will be evident. Young and aged male Fischer 344 rats were exposed to von Frey filaments (0.07g – 26g) applied sequentially to primary, secondary, and tertiary regions of dorsal skin as determined in previous studies. Cutaneous trunci muscle reflex (CTMR) to von Frey filament stimulation was recorded and Western blot analysis was used to measure expression of NR1 in spinal cord. The results showed that aged rats had significantly greater responses to punctate mechanical nociceptive stimulation than young rats; this age difference was more pronounced at higher filament forces. Punctate mechanical nociceptive stimulation increased spinal NR1 expression but this increase was statistically significant only in young rats. In aged rats, a statistically significant decrease in NR1 expression negatively correlated with the increased response to punctuate nociceptive stimulation. These results imply that age-related changes in sensitivity to mechanical nociceptive stimuli may be evoked by a mechanism involving the NMDA system. Supported by NIH T32AG020494.
Research consistently shows that healthy women experience a decrease in sensitivity to experimental pain stimuli during and following exercise. The mechanisms that underlie this exercise-induced hypoalgesia (EIH) are unknown. EIH reliably occurs at higher intensities and longer durations of exercise, levels that are often painful. Thus, it has been suggested that EIH results from an endogenous pain inhibitory mechanism termed conditioned pain modulation (CPM), similar to diffuse noxious inhibitory controls. The purpose of this study was to determine whether exercise-induced muscle pain serves as a CPM stimulus, testing one potential mechanism of EIH. Sixteen healthy women (mean age 30 yrs) completed pain testing during three counter-balanced sessions separated by one week: (1) 10 minutes of painful exercise on a cycle ergometer, (2) 10 minutes of non-painful exercise and (3) 10 minutes of quiet rest. All sessions included a 10-minute recovery period. Intensity and unpleasantness ratings in response to noxious thermal stimuli applied to the palm were assessed at baseline, at minutes 5, 7, and 9 of the experimental session and at minutes 5 and 10 of recovery. Data were analyzed with two linear mixed effects ANCOVAs with session and time serving as independent variables, pain intensity and unpleasantness as dependent variables and systolic blood pressure as the covariate of interest. Results showed a significant (p< 0.01) session by time interaction for both pain intensity and pain unpleasantness demonstrating that pain sensitivity decreased more quickly and to a greater extent during painful exercise than during either non-painful exercise or quiet rest. Moreover, sensitivity remained lower during recovery from painful exercise than the other sessions. These results suggest that naturally occurring leg muscle pain induced by exercise may contribute to EIH through CPM. Supported by a grant from the University of Wisconsin Virginia Horne Henry Fund.