痛覚、痒み、及びその障害 Pain, Itch and Their Disorders
P3-2-34 GDNFは青斑核において下行性ノルアドレナリン神経伝達を介して神経障害性疼痛を緩和する GDNF in the locus coeruleus alleviates neuropathic pain through descending noradrenergic inhibition ○木村茉莉子1,2, 坂井敦2, 坂本篤裕1, 鈴木秀典2 ○Mariko Kimura1,2, Atsushi Sakai2, Atsuhiro Sakamoto1, Hidenori Suzuki2 日本医大院・疼痛制御麻酔科学1, 日本医大院・薬理2 Dept Anethesiol, Grad Sch, Nippon Med Sch, Tokyo1, Dept Pharmacol, Grad Sch, Nippon Med Sch, Tokyo2 Locus coeruleus (LC) constitutes a descending noradrenergic pain-modulating pathway, through which the brain inhibits nociceptive transmission at the spinal cord. Therefore, the noradrenergic system has been considered a possible target for analgesics. In fact, conventional noradrenergic drugs are useful for intractable neuropathic pain, which results from damage to sensory system itself. However, because of their serious systemic adverse effects, other strategy enhancing noradrenergic descending inhibition has a potential for an appropriate medication. Glial cell line-derived neurotrophic factor (GDNF) is known to support the survival and functions of noradrenergic neurons. Therefore, we assessed the effects of GDNF in the LC on the neuropathic pain. To deliver GDNF to LC, a guide cannula was implanted to 7-week-old male rats. Five to seven days later, chronic constriction injury (CCI) was made on the left sciatic nerve. GDNF was injected once a day from days 7 to 9 after CCI. Mechanical allodynia and thermal hyperalgesia were examined by the von Frey and Plantar tests, respectively. Injection of GDNF into the left LC showed no acute effects on neuropathic pain. However, both mechanical allodynia and thermal hyperalgesia were significantly attenuated at 2 days after the beginning of GDNF injection in a dose-dependent manner. The analgesic effects continued for at least 3 days after the last GDNF injection. To validate whether the analgesic effects of GDNF is mediated by descending noradrenergic transmission, an α2-adrenoceptor antagonist, yohimbine, was intrathecally injected. After yohimbine administration, the analgesic effect of GDNF was abolished. These results suggest that GDNF in the LC exerts the analgesic effects on neuropathic pain through descending noradrenergic transmission. Enhancing GDNF signaling may provide a new analgesic strategy to enhance noradrenergic transmission rather than direct excitation of adrenergic receptors.	P3-2-35 ラット脊髄後角で低閾値機械受容線維とコンタクトしている興奮性及び抑制性II層インターニューロン群 Populations of excitatory and inhibitory lamina II interneurons contacting with terminals of putative low-threshold mechanoreceptive afferents in the rat spinal dorsal horn ○八坂敏一1, 藤田亜美1, 熊本栄一1 ○Toshiharu Yasaka1, David I Hughes2, John S Riddell2, Tsugumi Fujita1, Eiichi Kumamoto1, Andrew J Todd2 佐賀大・医・生体構造機能1 Dept Anat & Physiol, Facult Med, Saga Univ, Saga, Japan1, CMVLS, Univ of Glasgow, Glasgow, UK2 The lamina II of the spinal dorsal horn is known to play a role in modulating and transmitting incoming sensory (including nociceptive) information. However, its structural and functional organization, and its role in the neuronal circuitry for processing pain information, remain poorly understood due to the difficulty in identifying populations of interneurons. Virtually all SG neurons are excitatory or inhibitory interneurons because none of the axons arising from these cells reach supraspinal areas. Thus it is very important to dissect the local neuronal circuitry, which involves different types of lamina II neurons, in order to understand the output signal from spinal cord. Recently, we investigated these interneurons by using a combined electrophysiological and anatomical approach. This included tests for discharge patterns, responses to neuromodulators, and excitatory and inhibitory inputs evoked by dorsal root stimuli, as well as examination of morphological features and neurochemical phenotypes. We found substantial correlations among these properties. We also revealed possible mechanisms involving abnormal pain states. For example, we found a possibility that vertical cells (excitatory interneurons) might convey signals from low-threshold mechanoreceptive afferents to lamina I projection neurons because vertical cells had dendrites contacting with myelinated primary afferents in laminae III/IV and axons synapse onto lamina I projection cells. In this study, we investigated which type of inhibitory interneuron formed axo-axonic synapses in inner lamina II and lamina III because they are thought to be involved in presynaptic inhibition at central terminals of certain primary afferents. It is likely that particular types of lamina II neurons have specific roles in modulating local circuitry, so that the input-output relation could be changed through interactions among different types of interneurons.
P3-2-36 The rat formalin nociception assay: Examination of putative analgesic effects of traditional medicines Yan Hu Suo, Wei Ling Xian, San Qi, and Xu Duan ○Eric Wiertelak1, Erin Gaidis1 Macalester College1 Traditional (here, Chinese) medicine has many formulations intended to reduce pain and suffering, yet few have been investigated using western neuropharmacological animal model methods. We examined the effects of four plants: Yan Hu Suo (Rhizoma corydalis), Wei Ling Xian (Radix clematidis), San Qi (Panax pseudoginseng), and Xu Duan (Radix dipsaci asperi) in the rat formalin nociceptive assay. Animal responses in this assay correlate with human indices of pain responsive to opiate analgesics, and here may reveal mechanisms of action involving descending opiate or other neuromodulatory circuitry. All methods were approved by the Macalester Institutional Animal Care and Use Committee. For each study, 16 female, adult rats were randomly divided into 2 groups of 8. Experimental-group animals received 0.029g Yan Hu Suo, 0.035g Wei Ling Xian, 0.004g San Qi, or 0.059g Xu Duan, respectively (gavage, 30 minutes prior to formalin injection; all in 10mg/kg water suspension; control subjects received equivolume water alone). For the assay, 0.05ml of 5 percent formalin solution was injected into the dorsum of the subjects' right hind paw. Beginning five minutes after the injection, each subject was observed for number of times licking, shaking, or lifting of the injected paw for a 1 minute period at 5 minute intervals until 1 hour elapsed. Results: Wei Ling Xian produced no effects. Shaking behavior alone was significantly increased during the acute phase (here, defined as the initial 20 minutes) in rats given San Qi. All behaviors were significantly decreased in the acute phase only in rats given Xu Duan. However, shaking and licking were significantly decreased in the acute phase, and licking during the tonic phase (here, defined as the latter 40 minutes) in rats given Yan Hu Suo. Additional dose-response studies focusing on Yan Hu Suo will be completed, including naltrexone challenge of the effect to examine potential opiate circuitry mediation.	P3-2-37 Neuropathic pain caused by mutant glycyl-tRNA synthetase in Charcot-Marie-Tooth disease ○Seojin Lee1, Youn Ho Shin1, Byung Sun Park1, Junyang Jung1, Youngbhum Huh1 Kyung Hee University1 Charcot-Marie-Tooth disease(CMT) is the one of the most common inherited neuropathy. Mutant glycyl-tRNA synthetase (GARS) belonged to aminoacyl-tRNA synthetase are related to CMT pathogenesis. In this study, we set up the neuropathic pain-mimic animal model system by constructing GARS mutated virus vectors. Using viral vector to animal, we analyzed expression pattern of viral vectors in spinal cord and sciatic nerves through histoanatomical, functional and molecular biological methods. We use sciatic nerve infection system which is the best way to induce CMT2D and check to identify the phenotype of spinal dorsal horn after mutant GARS infection. These findings suggest that this mimic model system may play a important role for identifying the pathogenesis of neuropathic pain in CMT2D and affect the development of CMT treatment.
P3-2-38 Modulation of morphine antinoceptive tolerance in bone cancer pain rats by P2X7 purinoceptor ○HUI LI1 Fudan University1 Bone cancer pain is the most severe chronic pain, and morphine is the most effective analgesic. However, long-term morphine therapy produces morphine antinociceptive tolerance. So far, studies on morphine tolerance are mostly carried out in normal animals , despite that the clinical morphine antinociceptive tolerance occurs only in patients with chronic pain.Actually,chronic pathological pain is quite different from normal physiological pain in mechanisms.Therefore it is more meaningful to study the mechanisms of morphine tolerance in chronic pain animal models. Neuroinflammation plays an important role in the development of both chronic pain and morphine tolerance. For the firsr time, we investigate the role of P2X7 purinoceptor-mediated the activation of spinal microglial P38/MAPK signaling pathway,proinflammatory cytokines (e.g. IL-1beta and IL-18) and astrocytic products (e.g. D-Serine) release, and hypersensitivity of spinal dorsal horn neurons in morphine tolerance in a rat model of bone cancer pain. Our data showed that the chronic morphine treatment for 10 days resulted in a significant loss of analgesic potency in both mechanical and thermal nociceptive tests in rats suffered from bone cancer pain. The expression levels of P2X7R, Ibal-1, IL-18 and IL-1betain the spinal dorsal horn were remarkably increased, both in bone cancer rats and chronic morphine treated naive rats. Interestingly, in chronic morphine treated bone cancer rats, spinal Ibal-1 and IL-18 levels were much lower than bone cancer rats without chronic morphine treatment and naive rats chronic with morphine treatment. These results suggest that in chronic pathological pain status, the mechanism of morphine tolerance is more complicated.	P3-2-39 Depressive-like behaviour induced by neuropathic pain of infraorbital nerve constriction in rats ○Huan Qing Guo1 Fudan University1 Chronic neuropathic pain often induces mood disorders such as anxiety and depressive disorders.So far,there are many studies show that chronic pain have explicit relationship with the rate of depression. Depression is a devastating disease with a course that is chronic or recurrent and affects millions of people. In recent years,more and more people suffered from depression, so it is very important and imminently to search an effective therapeutic for depression. Infraorbital nerve constriction in rat can trigger prolonged neuropathic pain. Prolonged neuropathic pain induces mood disorder, and then increases the rate of depression. Many studies show that after infraorbital nerve constriction,the expression of microglia and immunocyte obviously increased. The development and maintenance of neuropathic pain associated with microglia and immunocyte expression. Learned helplessness(LH) lead to depression-like behavior in rat, many study have clarified LH increase the probability of depression-like behavior in rat with neuropathic pain. Also LH can boost mechanical allodynia in rat with neuropathic pain. It is very distinctly P2X7 receptor participates in the nociceptive transmission.We want to know whether the P2X7 receptor plays an important role in the comorbidity of chronic pain and depression? In our study,we focused on the relationship between depression and microglial activation. In the pathogenesis of neuropathic pain, a great quantity of microglia be activated and release pro-inflammatory cytokines and chemokines, these cytokines can regulate gene expression. If microglia and immunocyte expression related to depression, We will investigate that if P2X7R-mediated microglial activation is involved in the comorbidity of chronic pain and depression.
P3-2-40 Modulation of gastric motility by nociceptive input from the paraspinal muscles in urethane-anesthetised rats ○Mathieu Piche1,2, Watanabe Nobuhiro2, Hotta Harumi2 Universite du Quebec a Trois-Rivieres1, Dept. of Autonomic Neuroscience, Tokyo Metropolitan Insitute of Gerontology, Tokyo, Japan2 It is well known that somatic stimulation may alter autonomic functions. For instance, gastric motility may be increased by pinching of a hind paw by a supraspinal vagally-mediated reflex. In contrast, it may be decreased by pinching of the abdominal skin by a segmental sympathetic reflex. However, little is known about somato-gastric reflexes originating from spinal tissues. Since muscle pain from the back is common, the aim of this study was to investigate somato-gastric reflexes induced by paraspinal muscle stimulation. In 8 urethane-anesthetized rats, hypertonic saline (20μL;6%) was injected in paraspinal muscles to produce nociception in three spinal regions (T2,T13,L6), while gastric pressure was measured with a gastric balloon in three successive conditions: control, after vagotomy, after spinalisation at C1. An isotonic saline solution (20μL0.9%) was also injected in the same regions and conditions and served as a non nociceptive control stimulation. The non nociceptive stimulation did not produce any significant change in gastric pressure, for any condition and any region (p>0.05), except for T2, for which a small decrease was observed after spinalisation (p=0.04). Besides, the nociceptive stimulation did not produce any change in gastric pressure compared with the non nociceptive stimulation for any region, in the control condition or after vagotomy (p>0.01). After spinalisation, it was still ineffective when applied at T2 or L6 (p>0.05). However, a significant decrease of gastric pressure was observed when the nociceptive stimulation was applied at T13 (p=0.01). This indicates that nociceptive input from back muscles in the lower thoracic region, from which afferents can modulate sympathetic preganglionic neurons of the stomach, can decrease gastric motility by a spinal reflex, but only after descending inhibition has been removed. These results imply that back pain of muscular origin may not affect gastric motility in patients with an intact spinal cord.

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