- Email: [email protected]
109 MOLECULAR MECHANISMS FOR MODIFICATION OF SYNAPTIC TRANSMISSION OF AFFERENTS FOLLOWING PERIPHERAL NERVE INJURY
Invited Presentations / Workshop – Basic Sciences 5 / European Journal of Pain 11(S1) (2007) S1–S57
S43
The results of a big Latin American Pain Survey will be published soon so, we will be able to analyze the exact figures about this entity. Latin America has its own special problems in assessing, controlling and treating diabetes, more than 350 million people live in rural areas many times lacking even drinkable water. The basic medical services are also poor in health professionals, lab testing, medical and paramedical equipment and drugs for treating basic diseases such as diabetes. Nevertheless, many National Health Secretaries, WHO programs, NGO’s and other private Foundations have managed during the last 15 years to introduce programs and founds to diagnose and treat diabetes so, the numbers of diabetes neuropathy have decreased since these efforts. The idea of treating Diabetic Peripheral Neuropathic Pain (DPNP) is now very clear in the entire region. Starts lowering glucose levels then administrate pain killers, from Aspirin to all the other NSAID’s to Controlled Release Oxicodone (available just in a few cities of some countries). We know that almost half of all people with diabetes have some kind of neuropathy or nerve damage and this is associated with pain which can be difficult to treat, therefore we can start new assessment programs with early education, consequently a better comprehension of patient should be obtained as to what to expect when pain appears.
other regulated vesicle-associated molecules in the modification of synaptic transmission of afferents following peripheral nerve injury. In the spinal cord dorsal horn, Professor Yoshimura from Kyushu University in Japan will discuss the functional roles of the A-beta afferents sprouting in the spinal cord dorsal horn. Using the in vivo patch–clamp recordings, he will present the data supporting that the subpopulation of A-beta afferents may carry nociceptive information at least in immature state. Finally, in the anterior region of the prefrontal cortex, Professor Zhuo from University of Toronto in Canada will report a long-lasting increase in the synaptic efficacy (or LTP) in the ACC after nerve injury. Both presynaptic enhancement of glutamate release and increased postsynaptic AMPA receptor mediated responses contribute to nerve injury-induced LTP in the ACC. Genetic studies of the use of AC1 knockout mice suggest AC1 thus may serve as a novel target for treating neuropathic pain.
doi:10.1016/j.ejpain.2007.03.121
Institute of Neuroscience and Key Laboratory of Neurobiology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China
Workshop – Basic Sciences 5: MOLECULAR AND SYNAPTIC MECHANISMS FOR NEUROPATHIC PAIN
108 Workshop Summary: MOLECULAR AND SYNAPTIC MECHANISMS FOR NEUROPATHIC PAIN M. Zhuo Department of Physiology, University of Toronto, Canada Understanding molecular and cellular mechanisms of synaptic plasticity not only provides basic information for learning and memory, but also reveals potential new targets for treating disease including neuropathic pain. In this symposium, three speakers will provide their recent findings of injury-related plasticity along somatosensory pathways, from the dorsal root ganglion (DRG) cells to the anterior cingulate cortex (ACC). In the DRG level, Dr. Xu Zhang from Institute of Neuroscience in China will present the evidence for the upregulation of synaptoporin, an integral membrane component of synaptic vesicle, after nerve injury. He will also discuss the functions of
doi:10.1016/j.ejpain.2007.03.122
109 MOLECULAR MECHANISMS FOR MODIFICATION OF SYNAPTIC TRANSMISSION OF AFFERENTS FOLLOWING PERIPHERAL NERVE INJURY X. Zhang
The peripheral nerve injury-induced modification of the molecular basis of synaptic transmission at afferent terminals would contribute to the mechanisms of neuropathic pain. Using cDNA array, we find that the expression of twelve vesicle-associated molecules is strongly changed in rat dorsal root ganglion (DRG) after peripheral nerve injury. Synaptoporin and synaptophysin are integral membrane components of synaptic vesicles. Synaptoporin is expressed in subsets of small neurons that contain either neuropeptides or isolectin B4, and is distributed in their afferent terminals in laminae I–II of the spinal cord. Synaptophysin is expressed in 57% of synaptoporin-containing small DRG neurons and in large DRG neurons. In the spinal dorsal horn, synaptophysin-immunolabeling is weak in the afferents in laminae I–II, but strong in the afferents in laminae III–IV. Peripheral nerve injury increases synaptoporin expression in small DRG neurons and synaptoporin level in their afferent terminals. Thus, synaptoporin is a major synaptic vesicle protein in nociceptive afferents in both physiological and neuropathic pain states. We will also discuss the functions of other regulated vesicle-associated molecules in the modifica-
S44
Invited Presentations / Workshop – Mechanisms And Translational Research 5 / European Journal of Pain 11(S1) (2007) S1–S57
tion of synaptic transmission of afferents following peripheral nerve injury. doi:10.1016/j.ejpain.2007.03.123
110 ANALOGY OF A-BETA AFFERENTS TERMINATION IN PATHOLOGICAL CONDITIONS WITH IMMATURE STATE M. Yoshimura *,a, T. Nakatsuka b, H. Furue a a
Department of Integrative Physiology, Kyushu University, Fukuoka, Japan b Department of Physiology, Faculty of Medicine, Saga University, Saga-City, Japan Background and aims: The termination of primary afferents changes during maturation and pathological conditions, for instance, A-beta afferents terminate in lamina II (substantia gelatinosa; SG) in immature state, then retract to deeper laminae following maturation. After sciatic nerve transection or inflammation, the Abeta afferents sprout again into SG. The aims of this study are to clarify the functional role of the afferents at immature state and why the sprouting is triggered by peripheral injuries. Methods: Patch-clamp recordings were made from SG neurons from rat in vitro and in vivo preparations. Results: About 10% and 30% of SG neurons following the sciatic nerve transection and inflammation, respectively, received monosynaptic A-beta inputs, being analogous, at least in part with those of immature state. We, therefore, further tested whether the sprouted A-beta afferents retracted to the deeper laminae, with the behavioral changes 5 weeks after inflammation. Von Frey examination showed no difference in strength with normal; furthermore, the number of sprouted Abeta afferents significantly decreased to normal, suggesting that the reorganization of A-beta afferents is one of key factors producing pathological state. Therefore, next we tested a functional role of A-beta afferents in immature state using in vivo patch-clamp recordings. All dorsal roots, except a root that elicited only A-beta response in SG by stimulating the root were cut, then the receptive field was mechanically stimulated. Two of three neurons responded to pinch, suggesting that the subpopulation of A-beta afferents carry nociceptive information at least in immature state.
M. Zhuo Department of Physiology, University of Toronto, Canada The anterior cingulate cortex (ACC) plays a critical role in the pain perception and emotional unpleasantness in humans and animals. We have proposed that longterm potentiation (LTP) in the ACC may serve as a neuronal basis for injury-related long-term plastic changes in the ACC. Under experimental conditions, LTP induced by different induction protocols in the ACC of brain slices seems to be mediated solely by postsynaptic mechanism. The postsynaptic enhancement of glutamate AMPA receptor-mediated excitatory responses contribute to ACC LTP, in part due to the possible trafficking of AMPA GluR1 subunit after LTP induction. However, it is unclear if postsynaptic LTP may mimic pathological pain conditions. Here we report a long-lasting increase in the synaptic efficacy (or LTP) in the ACC after nerve injury using a brain slice preparation. Both presynaptic enhancement of glutamate release as well as increased postsynaptic AMPA receptor mediated responses contribute to nerve injury-induced LTP in the ACC. This finding differs from pure postsynaptic expression of ACC LTP induced by experimental electrical stimulation. Gene deletion of AC1, a key calcium-calmodulin stimulated adenylyl cyclase, abolished or significantly reduced presynaptic and postsynaptic effects. In parallel, behavioral allodynia induced nerve injury was also reduced in AC1 gene knockout mice. Our results provide the first pathological evidence for mixed presynaptic and postsynaptic forms of LTP in neuropathic pain, and demonstrate that AC1 as a key signaling molecule for central plasticity and neuropathic allodynia. AC1 thus may serve as a novel target for treating neuropathic pain. doi:10.1016/j.ejpain.2007.03.125
Workshop – Mechanisms And Translational Research 5: THE ROLE OF ENDOGENOUS PAIN CONTROL IN NEUROPATHIC PAIN – EVIDENCE FROM RLS
112 Workshop Summary: DOPAMINERGIC MECHANISMS OF PAIN CONTROL A.I. Basbaum *,a, W. Magerl b a
doi:10.1016/j.ejpain.2007.03.124
111 ENHANCED PRESYNAPTIC AND POSTSYNAPTIC EXCITATORY TRANSMISSION IN THE ACC AFTER NERVE INJURY
Department of Anatomy, University of California San Francisco, USA b Institute of Physiology, Johannes Gutenberg-University, Mainz, Germany Although alterations in endogenous pain control systems have been implicated in neuropathic pain condi-
S43
The results of a big Latin American Pain Survey will be published soon so, we will be able to analyze the exact figures about this entity. Latin America has its own special problems in assessing, controlling and treating diabetes, more than 350 million people live in rural areas many times lacking even drinkable water. The basic medical services are also poor in health professionals, lab testing, medical and paramedical equipment and drugs for treating basic diseases such as diabetes. Nevertheless, many National Health Secretaries, WHO programs, NGO’s and other private Foundations have managed during the last 15 years to introduce programs and founds to diagnose and treat diabetes so, the numbers of diabetes neuropathy have decreased since these efforts. The idea of treating Diabetic Peripheral Neuropathic Pain (DPNP) is now very clear in the entire region. Starts lowering glucose levels then administrate pain killers, from Aspirin to all the other NSAID’s to Controlled Release Oxicodone (available just in a few cities of some countries). We know that almost half of all people with diabetes have some kind of neuropathy or nerve damage and this is associated with pain which can be difficult to treat, therefore we can start new assessment programs with early education, consequently a better comprehension of patient should be obtained as to what to expect when pain appears.
other regulated vesicle-associated molecules in the modification of synaptic transmission of afferents following peripheral nerve injury. In the spinal cord dorsal horn, Professor Yoshimura from Kyushu University in Japan will discuss the functional roles of the A-beta afferents sprouting in the spinal cord dorsal horn. Using the in vivo patch–clamp recordings, he will present the data supporting that the subpopulation of A-beta afferents may carry nociceptive information at least in immature state. Finally, in the anterior region of the prefrontal cortex, Professor Zhuo from University of Toronto in Canada will report a long-lasting increase in the synaptic efficacy (or LTP) in the ACC after nerve injury. Both presynaptic enhancement of glutamate release and increased postsynaptic AMPA receptor mediated responses contribute to nerve injury-induced LTP in the ACC. Genetic studies of the use of AC1 knockout mice suggest AC1 thus may serve as a novel target for treating neuropathic pain.
doi:10.1016/j.ejpain.2007.03.121
Institute of Neuroscience and Key Laboratory of Neurobiology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China
Workshop – Basic Sciences 5: MOLECULAR AND SYNAPTIC MECHANISMS FOR NEUROPATHIC PAIN
108 Workshop Summary: MOLECULAR AND SYNAPTIC MECHANISMS FOR NEUROPATHIC PAIN M. Zhuo Department of Physiology, University of Toronto, Canada Understanding molecular and cellular mechanisms of synaptic plasticity not only provides basic information for learning and memory, but also reveals potential new targets for treating disease including neuropathic pain. In this symposium, three speakers will provide their recent findings of injury-related plasticity along somatosensory pathways, from the dorsal root ganglion (DRG) cells to the anterior cingulate cortex (ACC). In the DRG level, Dr. Xu Zhang from Institute of Neuroscience in China will present the evidence for the upregulation of synaptoporin, an integral membrane component of synaptic vesicle, after nerve injury. He will also discuss the functions of
doi:10.1016/j.ejpain.2007.03.122
109 MOLECULAR MECHANISMS FOR MODIFICATION OF SYNAPTIC TRANSMISSION OF AFFERENTS FOLLOWING PERIPHERAL NERVE INJURY X. Zhang
The peripheral nerve injury-induced modification of the molecular basis of synaptic transmission at afferent terminals would contribute to the mechanisms of neuropathic pain. Using cDNA array, we find that the expression of twelve vesicle-associated molecules is strongly changed in rat dorsal root ganglion (DRG) after peripheral nerve injury. Synaptoporin and synaptophysin are integral membrane components of synaptic vesicles. Synaptoporin is expressed in subsets of small neurons that contain either neuropeptides or isolectin B4, and is distributed in their afferent terminals in laminae I–II of the spinal cord. Synaptophysin is expressed in 57% of synaptoporin-containing small DRG neurons and in large DRG neurons. In the spinal dorsal horn, synaptophysin-immunolabeling is weak in the afferents in laminae I–II, but strong in the afferents in laminae III–IV. Peripheral nerve injury increases synaptoporin expression in small DRG neurons and synaptoporin level in their afferent terminals. Thus, synaptoporin is a major synaptic vesicle protein in nociceptive afferents in both physiological and neuropathic pain states. We will also discuss the functions of other regulated vesicle-associated molecules in the modifica-
S44
Invited Presentations / Workshop – Mechanisms And Translational Research 5 / European Journal of Pain 11(S1) (2007) S1–S57
tion of synaptic transmission of afferents following peripheral nerve injury. doi:10.1016/j.ejpain.2007.03.123
110 ANALOGY OF A-BETA AFFERENTS TERMINATION IN PATHOLOGICAL CONDITIONS WITH IMMATURE STATE M. Yoshimura *,a, T. Nakatsuka b, H. Furue a a
Department of Integrative Physiology, Kyushu University, Fukuoka, Japan b Department of Physiology, Faculty of Medicine, Saga University, Saga-City, Japan Background and aims: The termination of primary afferents changes during maturation and pathological conditions, for instance, A-beta afferents terminate in lamina II (substantia gelatinosa; SG) in immature state, then retract to deeper laminae following maturation. After sciatic nerve transection or inflammation, the Abeta afferents sprout again into SG. The aims of this study are to clarify the functional role of the afferents at immature state and why the sprouting is triggered by peripheral injuries. Methods: Patch-clamp recordings were made from SG neurons from rat in vitro and in vivo preparations. Results: About 10% and 30% of SG neurons following the sciatic nerve transection and inflammation, respectively, received monosynaptic A-beta inputs, being analogous, at least in part with those of immature state. We, therefore, further tested whether the sprouted A-beta afferents retracted to the deeper laminae, with the behavioral changes 5 weeks after inflammation. Von Frey examination showed no difference in strength with normal; furthermore, the number of sprouted Abeta afferents significantly decreased to normal, suggesting that the reorganization of A-beta afferents is one of key factors producing pathological state. Therefore, next we tested a functional role of A-beta afferents in immature state using in vivo patch-clamp recordings. All dorsal roots, except a root that elicited only A-beta response in SG by stimulating the root were cut, then the receptive field was mechanically stimulated. Two of three neurons responded to pinch, suggesting that the subpopulation of A-beta afferents carry nociceptive information at least in immature state.
M. Zhuo Department of Physiology, University of Toronto, Canada The anterior cingulate cortex (ACC) plays a critical role in the pain perception and emotional unpleasantness in humans and animals. We have proposed that longterm potentiation (LTP) in the ACC may serve as a neuronal basis for injury-related long-term plastic changes in the ACC. Under experimental conditions, LTP induced by different induction protocols in the ACC of brain slices seems to be mediated solely by postsynaptic mechanism. The postsynaptic enhancement of glutamate AMPA receptor-mediated excitatory responses contribute to ACC LTP, in part due to the possible trafficking of AMPA GluR1 subunit after LTP induction. However, it is unclear if postsynaptic LTP may mimic pathological pain conditions. Here we report a long-lasting increase in the synaptic efficacy (or LTP) in the ACC after nerve injury using a brain slice preparation. Both presynaptic enhancement of glutamate release as well as increased postsynaptic AMPA receptor mediated responses contribute to nerve injury-induced LTP in the ACC. This finding differs from pure postsynaptic expression of ACC LTP induced by experimental electrical stimulation. Gene deletion of AC1, a key calcium-calmodulin stimulated adenylyl cyclase, abolished or significantly reduced presynaptic and postsynaptic effects. In parallel, behavioral allodynia induced nerve injury was also reduced in AC1 gene knockout mice. Our results provide the first pathological evidence for mixed presynaptic and postsynaptic forms of LTP in neuropathic pain, and demonstrate that AC1 as a key signaling molecule for central plasticity and neuropathic allodynia. AC1 thus may serve as a novel target for treating neuropathic pain. doi:10.1016/j.ejpain.2007.03.125
Workshop – Mechanisms And Translational Research 5: THE ROLE OF ENDOGENOUS PAIN CONTROL IN NEUROPATHIC PAIN – EVIDENCE FROM RLS
112 Workshop Summary: DOPAMINERGIC MECHANISMS OF PAIN CONTROL A.I. Basbaum *,a, W. Magerl b a
doi:10.1016/j.ejpain.2007.03.124
111 ENHANCED PRESYNAPTIC AND POSTSYNAPTIC EXCITATORY TRANSMISSION IN THE ACC AFTER NERVE INJURY
Department of Anatomy, University of California San Francisco, USA b Institute of Physiology, Johannes Gutenberg-University, Mainz, Germany Although alterations in endogenous pain control systems have been implicated in neuropathic pain condi-