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Genetic mechanisms underlying individual differences in pain and negative emotion
Abstracts / Neuroscience Research 71S (2011) e6–e44
e43
demonstrated that during the long course of chronic pain, such potentiation is finally consolidated through morphofunctional plastic changes and indeed alters the sensitivity and threshold for fear conditioning. These findings support the notion that the amygdala is one of the most prototypical essential kernels of the pain signaling system. Research fund: KAKENHI 21390436.
ONE, 2009). These findings provide valuable information that will open new avenues for personalized pain treatment and understanding genetic mechanisms of individual differences in pain and negative emotion. Research fund: KAKENHI 20390162.
doi:10.1016/j.neures.2011.07.187
S4-J-1-1 Mirror neuron and corporeal awareness
doi:10.1016/j.neures.2011.07.189
Akira Murata
S4-I-1-3 Role of the bed nucleus of the stria terminalis in pain-induced negative emotion Masabumi Minami Department of Pharmacol., Grad. Sch. of Pharm. Sci., Hokkaido University, Sapporo, Japan Pain is an unpleasant sensory and emotional experience. The neural systems underlying the sensory component of pain have been studied extensively, but we are only beginning to understand those underlying the affective component of pain. To assess the negative affective component of pain in animals, we used the place-conditioning paradigm. This protocol is based on an associative learning between the affective state and neutral environmental cues and widely used to examine the rewarding or aversive effects of drugs and non-pharmacological treatments. It is likely that the conditioned place aversion (CPA) induced by a painful stimulus in this paradigm reflects an aspect of the negative affective component of pain. The bed nucleus of the stria terminalis (BNST) is a limbic structure involved in stress responses and negative affective states such as anxiety and fear. Corticotropin-releasing factor (CRF) is also implicated in stress responses, and many CRF-immunoreactive fibers exist in the dorsolateral BNST (dlBNST). In the present study, we investigated the involvement of CRF within the dlBNST in pain-induced aversion using a conditioned place paradigm in male Sprague-Dawley rats. Intra-dlBNST injection of alpha-helical CRF, a CRF receptor antagonist, significantly suppressed the formalin-induced conditioned place aversion (F-CPA) without affecting nociceptive behaviors. Intra-dlBNST injection of CRF dosedependently produced CPA even in the absence of noxious stimulation. This CRF-induced CPA was reversed by the co-injection of Rp-cyclic adenosine monophosphorothioate (Rp-cAMPS), a selective PKA inhibitor. Intra-dlBNST injection of Rp-cAMPS, a protein kinase A (PKA) inhibitor, also attenuated the pain-induced CPA. Taken together, these results suggest that PKA activation by CRF within the dlBNST is crucial for the negative affective component of pain.
Dep. of Physiol., Kinki University Facul. of Med., Osakasayama, Japan Mirror neurons represent other’s visual action onto own motor representation. The most important theory of mirror neurons is simulation of other’s internal state in one’s own brain. On basis of this idea, mirror neuron system is considered to be neural correlate of the social cognitive function, like as communication, imitation, empathy and theory of mind. On the other hand, since mirror neurons were found in the motor control system, it is also important to consider functional meaning in the motor control. In this paper, I would like to consider functional correlation of mirror neurons system with corporeal awareness that has close relationship with motor control. Ongoing limb movement is monitored by actual sensory feedback and internal motor signal (efference copy) to establish more precise movement. The sense of agency is the sense that occurs only during voluntary movement. This implies that efference copy have a crucial role for the sense of agency. If the efference copy matches with actual sensory feedback in the comparator, the action is detected as self-generated. The network for sensory motor control involves parietal cortex and premotor cortex may have important role for sense of agency. I would suggest that mirror neurons are related in this system. Furthermore, mirror neurons implies that there are some mechanisms for recognition of other’s body in the brain. In the parietal cortex, there are several areas where visual-tactile bimodal neurons are found, that may be related to coding of own body parts and peripersonal space. We expect that a map of self-body parts is referred for recognition of other’s body. Actually, we found that some of bimodal neurons in parietal cortex represented both one’s own body and others’. Our data will provide important idea for matching system between one’s own body and others’ on the basis of the overlap of motor control system and mirror neuron system. Research fund: Grant-in-Aid for Scientific Research on Priority Areas, 20033022, 18047026. doi:10.1016/j.neures.2011.07.190
doi:10.1016/j.neures.2011.07.188
S4-J-1-2 Beyond action understanding: Mirror neuron system and selective assimilation of other’s action into self
S4-I-1-4 Genetic mechanisms underlying individual differences in pain and negative emotion
Sotaro Shimada
Kazutaka Ikeda 1 , Daisuke Nishizawa 1 , Shinya Kasai 1 , Kenichi Fukuda 2 , Masakazu Hayashida 3 1 Res. Project for Addictive Substances, Tokyo Metropolitan Inst. of Med. Sci., Tokyo, Japan 2 Suidoubashi Hosp., Tokyo Dental College, Tokyo, Japan 3 Dep. Anesthesiol., Juntendo University, Tokyo, Japan
Pain and subsequent negative emotion are the fundamental alart system, which is necessary for self-defense. Since the system is fundamental, a large part of the system is considered to be programmed in the genes. There are significant individual differences in pain sensitivity. In addition to the pain system, the system for analgesia, which relieves excessive pain, exists in our bodies. The system can be activated by analgesics such as morphine and fentanyl, and sensitivity to analgesics is also different among individuals. These individual differences in sensitivities to pain and analgesics can hamper effective pain control. Genetic factors are considered to be involved in the mechanisms of these individual differences. To elucidate the genetic mechanisms, we first investigated the mechanisms responsible for interstrain differences in sensitivity to pain and analgesics in mice. We found that a 5.3 kb nucleotide insertion in the 3 noncoding region of the -opioid receptor gene (Oprm1) caused a significant reduction in morphine-induced analgesia in CXBK mice. Additionally, in weaver mutant mice possessing a mutation in the gene encoding G-protein-activated inwardly rectifying potassium (GIRK) channel subunit 2 (Kcnj6), ethanol and morphine were less effective at reducing thermal nociception than in control mice. We then examined associations between polymorphisms of the corresponding genes and postoperative opioid requirements in humans. We found that two polymorphisms, A118G and IVS3+A8449G, in the human OPRM1 gene and a polymorphism, A1032G, in the human KCNJ6 gene were significantly associated with postoperative opioid requirements (Hayashida et al., Pharmacogenomics, 2008; Fukuda et al., Pain, 2009; Nishizawa et al., PLoS
Sch. Sci. Tech., Meiji University Kanagawa, Japan It is well established that several motor areas, called the mirror neuron system (MNS), are activated when an individual observes other’s action as well as when they performed the same action themselves. The most prominent functionality of MNS is often considered as a ‘deeper’ understanding of other’s action. That is, by internally simulating other’s action using their own motor representation, the observer can grasp the internal state of others, such as intention and affect. Recent MNS studies, however, have shown that MNS does not always activate equally when observing other’s actions even though the action is adequately understandable, but its activity is affected by several factors. These results seem to require an alternative or additional account for MNS functionality beyond the mere action understanding account. Here, two series of studies that demonstrated modulation of MNS activity during action observation are introduced. The first series of studies employed an experimental paradigm in which the subject watched a competitive game, being instructed to root for a particular player in the game. The result showed that MNS was more activated when the subject’s favored player won, compared with when this player lost or drew (Shimada & Abe, 2009; 2010), indicating the importance of the outcome for the observed action. A different series of studies showed that MNS was more activated when watching an action with a subtle mistake relative to a normal action (Shimada, 2009), suggesting kinematics of the action affects MNS activity. In order to account for these results, we propose a speculative hypothesis that MNS activity during action observation is affected by the difference between the observed and the expected actions, which would be a basis for observational motor learning. Research fund: KAKENHI (22118508, 22240026). doi:10.1016/j.neures.2011.07.191
e43
demonstrated that during the long course of chronic pain, such potentiation is finally consolidated through morphofunctional plastic changes and indeed alters the sensitivity and threshold for fear conditioning. These findings support the notion that the amygdala is one of the most prototypical essential kernels of the pain signaling system. Research fund: KAKENHI 21390436.
ONE, 2009). These findings provide valuable information that will open new avenues for personalized pain treatment and understanding genetic mechanisms of individual differences in pain and negative emotion. Research fund: KAKENHI 20390162.
doi:10.1016/j.neures.2011.07.187
S4-J-1-1 Mirror neuron and corporeal awareness
doi:10.1016/j.neures.2011.07.189
Akira Murata
S4-I-1-3 Role of the bed nucleus of the stria terminalis in pain-induced negative emotion Masabumi Minami Department of Pharmacol., Grad. Sch. of Pharm. Sci., Hokkaido University, Sapporo, Japan Pain is an unpleasant sensory and emotional experience. The neural systems underlying the sensory component of pain have been studied extensively, but we are only beginning to understand those underlying the affective component of pain. To assess the negative affective component of pain in animals, we used the place-conditioning paradigm. This protocol is based on an associative learning between the affective state and neutral environmental cues and widely used to examine the rewarding or aversive effects of drugs and non-pharmacological treatments. It is likely that the conditioned place aversion (CPA) induced by a painful stimulus in this paradigm reflects an aspect of the negative affective component of pain. The bed nucleus of the stria terminalis (BNST) is a limbic structure involved in stress responses and negative affective states such as anxiety and fear. Corticotropin-releasing factor (CRF) is also implicated in stress responses, and many CRF-immunoreactive fibers exist in the dorsolateral BNST (dlBNST). In the present study, we investigated the involvement of CRF within the dlBNST in pain-induced aversion using a conditioned place paradigm in male Sprague-Dawley rats. Intra-dlBNST injection of alpha-helical CRF, a CRF receptor antagonist, significantly suppressed the formalin-induced conditioned place aversion (F-CPA) without affecting nociceptive behaviors. Intra-dlBNST injection of CRF dosedependently produced CPA even in the absence of noxious stimulation. This CRF-induced CPA was reversed by the co-injection of Rp-cyclic adenosine monophosphorothioate (Rp-cAMPS), a selective PKA inhibitor. Intra-dlBNST injection of Rp-cAMPS, a protein kinase A (PKA) inhibitor, also attenuated the pain-induced CPA. Taken together, these results suggest that PKA activation by CRF within the dlBNST is crucial for the negative affective component of pain.
Dep. of Physiol., Kinki University Facul. of Med., Osakasayama, Japan Mirror neurons represent other’s visual action onto own motor representation. The most important theory of mirror neurons is simulation of other’s internal state in one’s own brain. On basis of this idea, mirror neuron system is considered to be neural correlate of the social cognitive function, like as communication, imitation, empathy and theory of mind. On the other hand, since mirror neurons were found in the motor control system, it is also important to consider functional meaning in the motor control. In this paper, I would like to consider functional correlation of mirror neurons system with corporeal awareness that has close relationship with motor control. Ongoing limb movement is monitored by actual sensory feedback and internal motor signal (efference copy) to establish more precise movement. The sense of agency is the sense that occurs only during voluntary movement. This implies that efference copy have a crucial role for the sense of agency. If the efference copy matches with actual sensory feedback in the comparator, the action is detected as self-generated. The network for sensory motor control involves parietal cortex and premotor cortex may have important role for sense of agency. I would suggest that mirror neurons are related in this system. Furthermore, mirror neurons implies that there are some mechanisms for recognition of other’s body in the brain. In the parietal cortex, there are several areas where visual-tactile bimodal neurons are found, that may be related to coding of own body parts and peripersonal space. We expect that a map of self-body parts is referred for recognition of other’s body. Actually, we found that some of bimodal neurons in parietal cortex represented both one’s own body and others’. Our data will provide important idea for matching system between one’s own body and others’ on the basis of the overlap of motor control system and mirror neuron system. Research fund: Grant-in-Aid for Scientific Research on Priority Areas, 20033022, 18047026. doi:10.1016/j.neures.2011.07.190
doi:10.1016/j.neures.2011.07.188
S4-J-1-2 Beyond action understanding: Mirror neuron system and selective assimilation of other’s action into self
S4-I-1-4 Genetic mechanisms underlying individual differences in pain and negative emotion
Sotaro Shimada
Kazutaka Ikeda 1 , Daisuke Nishizawa 1 , Shinya Kasai 1 , Kenichi Fukuda 2 , Masakazu Hayashida 3 1 Res. Project for Addictive Substances, Tokyo Metropolitan Inst. of Med. Sci., Tokyo, Japan 2 Suidoubashi Hosp., Tokyo Dental College, Tokyo, Japan 3 Dep. Anesthesiol., Juntendo University, Tokyo, Japan
Pain and subsequent negative emotion are the fundamental alart system, which is necessary for self-defense. Since the system is fundamental, a large part of the system is considered to be programmed in the genes. There are significant individual differences in pain sensitivity. In addition to the pain system, the system for analgesia, which relieves excessive pain, exists in our bodies. The system can be activated by analgesics such as morphine and fentanyl, and sensitivity to analgesics is also different among individuals. These individual differences in sensitivities to pain and analgesics can hamper effective pain control. Genetic factors are considered to be involved in the mechanisms of these individual differences. To elucidate the genetic mechanisms, we first investigated the mechanisms responsible for interstrain differences in sensitivity to pain and analgesics in mice. We found that a 5.3 kb nucleotide insertion in the 3 noncoding region of the -opioid receptor gene (Oprm1) caused a significant reduction in morphine-induced analgesia in CXBK mice. Additionally, in weaver mutant mice possessing a mutation in the gene encoding G-protein-activated inwardly rectifying potassium (GIRK) channel subunit 2 (Kcnj6), ethanol and morphine were less effective at reducing thermal nociception than in control mice. We then examined associations between polymorphisms of the corresponding genes and postoperative opioid requirements in humans. We found that two polymorphisms, A118G and IVS3+A8449G, in the human OPRM1 gene and a polymorphism, A1032G, in the human KCNJ6 gene were significantly associated with postoperative opioid requirements (Hayashida et al., Pharmacogenomics, 2008; Fukuda et al., Pain, 2009; Nishizawa et al., PLoS
Sch. Sci. Tech., Meiji University Kanagawa, Japan It is well established that several motor areas, called the mirror neuron system (MNS), are activated when an individual observes other’s action as well as when they performed the same action themselves. The most prominent functionality of MNS is often considered as a ‘deeper’ understanding of other’s action. That is, by internally simulating other’s action using their own motor representation, the observer can grasp the internal state of others, such as intention and affect. Recent MNS studies, however, have shown that MNS does not always activate equally when observing other’s actions even though the action is adequately understandable, but its activity is affected by several factors. These results seem to require an alternative or additional account for MNS functionality beyond the mere action understanding account. Here, two series of studies that demonstrated modulation of MNS activity during action observation are introduced. The first series of studies employed an experimental paradigm in which the subject watched a competitive game, being instructed to root for a particular player in the game. The result showed that MNS was more activated when the subject’s favored player won, compared with when this player lost or drew (Shimada & Abe, 2009; 2010), indicating the importance of the outcome for the observed action. A different series of studies showed that MNS was more activated when watching an action with a subtle mistake relative to a normal action (Shimada, 2009), suggesting kinematics of the action affects MNS activity. In order to account for these results, we propose a speculative hypothesis that MNS activity during action observation is affected by the difference between the observed and the expected actions, which would be a basis for observational motor learning. Research fund: KAKENHI (22118508, 22240026). doi:10.1016/j.neures.2011.07.191