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Minoru Kawamura - One of the best experts on this subject based on the ideXlab platform.
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Excitatory effect of Neurotropin® on noradrenergic neurons in rat locus coeruleus
Life sciences, 2015Co-Authors: Hisashi Okai, Ryohei Okazaki, Minoru Kawamura, Megumu YoshimuraAbstract:Abstract Aims Although the clinical use of Neurotropin ® as an analgesic for chronic pain has been firmly established, its analgesic mechanism is still unclear. In this study, we investigate the direct effects of Neurotropin using an electrophysiological method. Main methods Blind patch-clamp recordings were made from rat locus coeruleus (LC) and periaqueductal gray (PAG) neurons in brainstem slices of normal rats. The effects of intracerebroventricular (icv) injection of Neurotropin on nociceptive transmission were recorded from spinal substantia gelatinosa (SG) neurons in fifth lumbar spinal nerve-ligated (L5-SNL) rats using an in vivo patch-clamp method. Key findings Neurotropin (0.2–1.0 NU/mL) dose-dependently increased the firing rate in noradrenergic LC neurons of normal rats. Under the voltage-clamp condition, Neurotropin induced an inward current in 90% of LC neurons that was not affected by tetrodotoxin or an injection of GDP-β-S (G protein inhibitor) through recording pipettes. In contrast, Neurotropin had no effects on all PAG neurons tested. Using in vivo patch-clamp recordings, the icv injection of Neurotropin inhibited both frequency and amplitude of pinch-evoked excitatory postsynaptic currents of SG neurons in L5-SNL rats. These results suggest that Neurotropin directly excites the descending noradrenergic LC neurons and inhibits nociceptive transmission in the spinal dorsal horn. Significance This study is the first direct demonstration that Neurotropin activates the noradrenergic descending pain inhibitory systems, and this would reinforce the usefulness of Neurotropin in the treatment of human neuropathic pain.
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Combined antiallodynic effect of Neurotropin® and pregabalin in rats with L5-spinal nerve ligation.
Life sciences, 2013Co-Authors: Ryohei Okazaki, Hisashi Okai, Hiroyuki Yoshida, Hiroyoshi Namba, Kazuki Taguchi, Minoru KawamuraAbstract:In this study, we investigated the combined effect of Neurotropin® and pregabalin for L5-spinal nerve ligation (L5-SNL) model in rats and thiopental-induced sleep in mice. The left fifth lumbar nerve of rats was tightly ligated with silk sutures under pentobarbital anesthesia. The hindpaw withdrawal threshold was measured by application of von Frey filaments. Thiopental sodium was intravenously administered in mice and sleeping time was measured. In L5-SNL rats, an isobolographic analysis was performed to clarify the combined antiallodynic effect of Neurotropin and pregabalin 14 days after ligation in rats. In isobolographic analysis and thiopental-induced sleep test, Neurotropin and pregabalin were orally administered to coincide with the timing of the peak effect of each drug. Neurotropin (50-200 NU/kg) and pregabalin (2.5-10mg/kg) showed a dose-dependent antiallodynic action in L5-SNL rats. The antiallodynic effect of pregabalin was reversed by intrathecal injection of yohimbine or ondansetron. Isobolographic analysis suggested that the combined antiallodynic effect of Neurotropin and pregabalin in L5-SNL rats may have been more than a mere additive effect. Neurotropin (50-400 NU/kg) had no effect on thiopental-induced sleeping time whereas pregabalin (30-100mg/kg) significantly prolonged it. When the dose of pregabalin was 30 mg/kg, Neurotropin (50-400 NU/kg) did not further exacerbate the prolongation effect of pregabalin on thiopental-induced sleep. It was suggested that when Neurotropin was administered in combination with pregabalin, it might provide more effective pain relief than that obtained with each agent alone in neuropathic pain without aggravating adverse effects of pregabalin. Copyright © 2013 Elsevier Inc. All rights reserved.
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Combined antiallodynic effect of Neurotropin® and pregabalin in rats with L5-spinal nerve ligation.
Life Sciences, 2013Co-Authors: Ryohei Okazaki, Hisashi Okai, Hiroyuki Yoshida, Hiroyoshi Namba, Kazuki Taguchi, Minoru KawamuraAbstract:Abstract Aims In this study, we investigated the combined effect of Neurotropin® and pregabalin for L5-spinal nerve ligation (L5-SNL) model in rats and thiopental-induced sleep in mice. Main methods The left fifth lumbar nerve of rats was tightly ligated with silk sutures under pentobarbital anesthesia. The hindpaw withdrawal threshold was measured by application of von Frey filaments. Thiopental sodium was intravenously administered in mice and sleeping time was measured. In L5-SNL rats, an isobolographic analysis was performed to clarify the combined antiallodynic effect of Neurotropin and pregabalin 14 days after ligation in rats. In isobolographic analysis and thiopental-induced sleep test, Neurotropin and pregabalin were orally administered to coincide with the timing of the peak effect of each drug. Key findings Neurotropin (50–200 NU/kg) and pregabalin (2.5–10 mg/kg) showed a dose-dependent antiallodynic action in L5-SNL rats. The antiallodynic effect of pregabalin was reversed by intrathecal injection of yohimbine or ondansetron. Isobolographic analysis suggested that the combined antiallodynic effect of Neurotropin and pregabalin in L5-SNL rats may have been more than a mere additive effect. Neurotropin (50–400 NU/kg) had no effect on thiopental-induced sleeping time whereas pregabalin (30–100 mg/kg) significantly prolonged it. When the dose of pregabalin was 30 mg/kg, Neurotropin (50–400 NU/kg) did not further exacerbate the prolongation effect of pregabalin on thiopental-induced sleep. Significance It was suggested that when Neurotropin was administered in combination with pregabalin, it might provide more effective pain relief than that obtained with each agent alone in neuropathic pain without aggravating adverse effects of pregabalin.
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Mechanisms of analgesic action of Neurotropin on chronic pain in adjuvant-induced arthritic rat: roles of descending noradrenergic and serotonergic systems.
Journal of pharmacological sciences, 2005Co-Authors: Tomoshi Miura, Hisashi Okai, Ryohei Okazaki, Hiroyuki Yoshida, Hiroyoshi Namba, Minoru KawamuraAbstract:Neurotropin®, a non-protein extract from the inflamed skin of rabbits inoculated with vaccinia virus, has been clinically used as an analgesic drug for treatment of chronic pain. In this study, we investigated the analgesic mechanisms of Neurotropin in the adjuvant-induced arthritic rat, a chronic pain model with inflammation. Neurotropin caused dose-dependent inhibition of hyperalgesia in the adjuvant-induced arthritic rat after single intravenous (10 – 100 NU/kg) and oral (30 – 200 NU/kg) administration. The analgesic effect of Neurotropin (intravenous 100 NU/kg and oral 200 NU/kg) was significantly inhibited by intrathecal injections of the α2-adrenoceptor antagonist yohimbine (30 nmol/animal) and the selective 5-HT3 serotonin receptor antagonist MDL72222 (30 nmol/animal), and slightly inhibited by the non-selective serotonin receptor antagonist methysergide (100 nmol/animal). The results suggest that the analgesic action of Neurotropin is at least in part due to the enhancement of noradrenergic and serotonergic descending pain inhibitory pathways. Neurotropin may be useful for the clinical management of chronic pain diseases such as a rheumatoid arthritis and osteoarthritis.
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Neurotropin induces antinociceptive effect by enhancing descending pain inhibitory systems involving 5-HT3 and noradrenergic α2 receptors in spinal dorsal horn
Life sciences, 1998Co-Authors: Minoru Kawamura, Hiroyuki Ohara, Yutaka Koga, Kazuharu IenagaAbstract:Abstract Neurotropin, a non-protein extract from the inflamed skin of rabbits inoculated with vaccinia virus, has been clinically used as an analgesic drug in Japan. Its analgesic effect has been demonstrated by reduced mechano-nociception in hyperalgesic rats exposed to SART-stress (a repeated cold stress) for 5 days. In order to clarify the mechanism of the analgesic effect of Neurotropin at the spinal cord level, we examined the effects of several neurotransmitter receptor antagonists given by intrathecal (i.t.) injection on the antinociceptive effect of intraperitoneally (i.p.) injected Neurotropin [100 and 200 Neurotropin Unit (NU)/kg]. The analgesic effect of Neurotropin was significantly inhibited not only by methysergide (100 nmol Rat , i.t.), a non-selective antagonist against serotonin (5-HT), but also MDL 72222 (30 nmol Rat , i.t.), a selective 5-HT3 antagonist, but not influenced by ketanserin (100 nmol Rat , i.t.), a 5-HT2A antagonist. The antinociceptive effect of Neurotropin (200 NU Kg , i.p.) was significantly inhibited also by yohimbine (30 nmol Rat , i.t.), a noradrenergic α2 antagonist. However, the analgesic effect of Neurotropin (100 and 200 NU Kg , i.p.) was not influenced by naloxone (30 nmol Rat , i.t.), an opioid antagonist. These results suggest that the mechanism of the antinociceptive effect of Neurotropin is via enhancement of endogenous descending pain inhibitory pathways of the serotonergic and noradrenergic systems, especially involving 5-HT3 and noradrenergic α2 receptors in spinal dorsal horn in which these neurons terminate. No influence of opioid receptors at the spinal cord level is indicated.
Kazue Mizumura - One of the best experts on this subject based on the ideXlab platform.
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a single administration of Neurotropin reduced the elongated immobility time in the forced swimming test of rats exposed to repeated cold stress
Behavioural Pharmacology, 2019Co-Authors: Teruaki Nasu, Asako Kubo, Kazue Mizumura, Luis F QuemeAbstract:: Many people suffer from a major depressive disorder, and chronic pain conditions are often associated with depressive symptoms. Neurotropin, an extract from the inflamed skin of rabbits inoculated with vaccinia virus, has been used for pain relief. Decrease of brain-derived neurotrophic factor (BDNF) in the brain is one of the proposed mechanisms for the major depressive disorders, and Neurotropin has been reported to restore the decreased BDNF in the hippocampus. In this experiment, we examined whether Neurotropin had an antidepressant-like effect in a model of fibromyalgia and whether BDNF in the brain was altered after repeated cold stress (RCS) and Neurotropin treatment. Rats were exposed to RCS because these animals have been used as a model for fibromyalgia syndrome. Depression-like behavior was evaluated using elongation of immobility time in a forced swimming test. Change in expression of BDNF in the brain was also examined by western blot analysis of several brain areas. Depression-like behavior in the forced swimming test was significantly increased 10-14 days after RCS, and this increase was reversed by a single injection of an antidepressant, imipramine, but not by PBS. Increased depression-like behavior was also dose-dependently suppressed by a single administration of Neurotropin (50-200 NU/kg, subcutaneously). BDNF expression was not changed in the brain areas examined (hippocampus, amygdala, prefrontal cortex, and striatum) either after RCS or by Neurotropin injected after RCS. These results suggest that RCS induced a depression-like state in rats, and Neurotropin reversed this state. However, we did not observe a BDNF-related mechanism for these effects.
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Intramuscularly injected Neurotropin reduced muscular mechanical hyperalgesia induced by repeated cold stress in rats.
Behavioural pharmacology, 2018Co-Authors: Teruaki Nasu, Shiori Murase, Yoshiko Takeda-uchimura, Kazue MizumuraAbstract:An extract of rabbit skin inflamed by inoculation with the vaccinia virus, Neurotropin [by intravenous, oral, and intramuscular (i.m.) administration], has been used in China and Japan for the treatment of chronic pain. In this study, we investigated the analgesic mechanism of i.m. Neurotropin. Rats were exposed to repeated cold stress, and muscular mechanical hyperalgesia was evaluated by measuring the withdrawal threshold of the gastrocnemius muscle using Randall-Selitto apparatus. I.m. but not subcutaneous, Neurotropin dose dependently reduced the repeated cold stress-induced muscular mechanical hyperalgesia for 3 h, but it had no effect in normal rats. Injections of Neurotropin into the right gastrocnemius, quadriceps femoris, biceps brachii, and trapezius muscles reduced the muscular mechanical hyperalgesia of the gastrocnemius muscle bilaterally. Intrathecal administration of antagonists to GABAergic, serotonergic, and cholinergic receptors, but not α2-adrenergic receptors, and intraperitoneal administration of opioid receptor antagonist inhibited the analgesic effect of Neurotropin. These results indicated that an i.m. injection of Neurotropin induced long-lasting wide-spread bilateral muscular analgesia by activating spinal serotonergic and GABAergic receptors. As distinct from analgesia by systemic administration, spinal cholinergic and opioidergic, but not adrenergic receptors, are also involved. The present study supports the effectiveness of Neurotropin treatment for muscular mechanical hyperalgesia.
Michael K. Skinner - One of the best experts on this subject based on the ideXlab platform.
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Expression and Action of Neurotropin-3 and Nerve Growth Factor in Embryonic and Early Postnatal Rat Testis Development
Biology of reproduction, 2000Co-Authors: Andrea S. Cupp, Grace Kim, Michael K. SkinnerAbstract:The current study examines the expression and potential actions of Neurotropin-3 (NT3), nerve growth factor (NGF), and their receptors during morphological sex determination (seminiferous cord formation) and perinatal rat testis development. The expression of Neurotropins and their receptors was analyzed with immunohistochemistry. Cellular localization of Neurotropin ligand and receptor proteins changed during embryonic testis development. Neurotropin-3 was localized to Sertoli cells at Embryonic Day 14 (E14), was present in gonocytes at Postnatal Day 0 (P0), and after birth became localized to the interstitium and Sertoli cells (P3‐P5). The expression of trk C (the high affinity receptor for NT3) was localized to mesonephric ducts and cells surrounding the cords (E14‐E18). In addition, Sertoli cells and preperitubular cells surrounding the cords at E14 also stained for trk C. Neurotropin-3 was expressed in gonocytes and Sertoli cells at P0‐P5. Nerve growth factor was detected in Sertoli cells at E14, was clearly in Sertoli and interstitial cells at E16 and E18, and in Sertoli, germ, and interstitial cells from P0‐P5. The expression of trk A (the high affinity receptor for NGF) was located in Sertoli and interstitial cells at E16‐P5. To determine the actions of Neurotropins during embryonic and perinatal testis development, experiments were conducted on E13 and P0 testis. Antisense oligonucleotide experiments with NT3 were used on E13 testis organ cultures to determine effects on seminiferous cord formation. Cord formation was inhibited in 40% of the organ cultures treated with the antisense NT3 oligonucleotides, while no inhibition was observed with sense oligonucleotides. In P0 testis cultures, both NT3 and NGF alone and in combination stimulated thymidine incorporation into DNA. Therefore, the Neurotropins are involved in embryonic morphological events (cord formation; NT3) and in growth of the perinatal testis (P0; NT3 and NGF). To define further the growth effects of Neurotropins on testis development, expression of transforming growth factor alpha and beta (TGFa and TGFb) were examined in response to Neurotropins. The P0 testis cultures were treated with Neurotropins, and expression of mRNA for TGFa and TGFb was analyzed utilizing a quantitative reverse transcription-polymerase chain reaction assay. Nerve growth factor and NT3 alone or in combination inhibited expression of mRNA for TGFa while NT3 increased mRNA expression of epidermal growth factor receptor. The combination treatment of Neurotropins inhibited expression of TGFb1 and increased expression of TGFb3. In summary, observations suggest that NT3, NGF, trk A, and trk C are localized to cells critical to seminiferous cord formation and appear to be important regulators of morphological sex determination. In addition to these morphological effects, both NT3 and NGF stimulate P0 testis growth and may elicit their action through altering the expression of locally produced growth fac
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Role of Neurotropins in Rat Embryonic Testis Morphogenesis (Cord Formation)
Biology of reproduction, 2000Co-Authors: Elena Levine, Andrea S. Cupp, Michael K. SkinnerAbstract:The process of seminiferous cord formation is the first morphological event that differentiates a testis from an ovary and indicates male sex determination. Cord formation occurs by embryonic Day 14 (Day 0 5 plug date; E14) in the rat. A series of experiments were conducted to determine if Neurotropins and their receptors are important for the process of rat embryonic cord formation. The expression of low affinity Neurotropin receptor (p75/LNGFR) was determined by immunohistochemistry on sections of both testis and ovary from E13 through birth (Day 0, P0) with an antibody to p75/LNGFR. The staining for p75/ LNGFR was present in the mesonephros of E13 gonads and in a sex-specific manner appeared around developing cords at E14 in the embryonic testis. At birth, staining for p75/LNGFR was localized to a single layer of cells (i.e., peritubular cells) that surrounded the seminiferous cords. The genes for both Neurotropin 3 (NT3) and for corresponding high affinity Neurotropin trkC receptor were found to be expressed in the E14 rat testis, as well as other Neurotropins and receptors. Immunocytochemical analysis of E14 rat testis demonstrated that NT3 was localized to the Sertoli cells and trkC was present in individual cells of the interstitium at E16 and in selected preperitubular cells at E18. Previously, the peritubular cells adjacent to the cords were demonstrated to be derived from migrating mesonephros cells around the time of cord formation. To determine if Neurotropins were involved in cord formation, the actions of Neurotropins were inhibited. A high affinity Neurotropin receptor (trk)-specific kinase inhibitor, K252a, was used to treat organ cultures of testes from E13 rats prior to cord formation. Treatment of E13 testis organ cultures with K252a completely inhibited cord formation. K252a-treated organ cultures of E14 testis that contained cords did not alter cord morphology. A second experiment to inhibit Neurotropin actions utilized a specific antagonist trk-IgG chimeric fusion protein and E13 testis organ cultures. The trk-IgG molecules dimerize with endogenous trk receptors and inhibit receptor signaling and activation of ligand function. Forty percent of E13 testis organ cultures treated with trkC-IgG had significantly reduced cord formation. TrkA-IgG had no effect on initiation of cords; however, in fifty percent of the treated organs, a ‘‘swollen’’ appearance of the cord structures was observed. Experiments using trkB-IgG chimeric protein on E13 organ cultures had no effect on cord formation or cord morphology. The testes from trkC and NT3 knockout mice were ex
Ryozo Oishi - One of the best experts on this subject based on the ideXlab platform.
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Neurotropin® relieves oxaliplatin-induced neuropathy via Gi protein-coupled receptors in the monoaminergic descending pain inhibitory system
Life Sciences, 2014Co-Authors: Ken Masuguchi, Takehiro Kawashiri, Hitomi Watanabe, Nana Ozawa, Haruka Morita, Soichiro Ushio, Ryozo Oishi, Nobuaki EgashiraAbstract:Abstract Aims Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes acute and chronic peripheral neuropathies. We previously reported that repeated administration of Neurotropin prevents oxaliplatin-induced mechanical allodynia by inhibiting axonal degeneration in rats. In the present study, we investigated the analgesic effect of a single administration of Neurotropin on oxaliplatin-induced neuropathy in rats. Main methods Oxaliplatin (4 mg/kg) was administered intraperitoneally twice a week for 4 weeks. Cold hyperalgesia was assessed using the acetone test and mechanical allodynia was evaluated using the von Frey test. Key findings Repeated injection of oxaliplatin induced cold hyperalgesia on day 5 and mechanical allodynia on day 28. A single administration of Neurotropin transiently relieved both pain behaviors. The analgesic effect of Neurotropin was inhibited by pretreatment with 5-HT 1A , 5-HT 2 , 5-HT 3 , and α2 receptor antagonists and by monoamine depletion. Moreover, the analgesic effect of Neurotropin was abolished by intrathecal injection of pertussis toxin, a G i protein inhibitor. Significance These results suggest that Neurotropin is effective in relieving oxaliplatin-induced neuropathy, and that G i protein-coupled receptors in the monoaminergic descending pain inhibitory system may be involved in the analgesic effect of Neurotropin. Neurotropin may have clinical potential for the treatment of oxaliplatin-induced neuropathies.
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Prevention of oxaliplatin-induced mechanical allodynia and neurodegeneration by Neurotropin in the rat model
European Journal of Pain, 2010Co-Authors: Takehiro Kawashiri, Takahisa Yano, Hiroaki Ikesue, Hitomi Watanabe, Shingo Hirakawa, Yuki Mihara, Yoko Ikegami, Nobuaki Egashira, Ryozo OishiAbstract:Oxaliplatin is a key drug for colorectal cancer, but it causes acute peripheral neuropathy (triggered by cold) and chronic neuropathy (sensory and motor neuropathy) in patients. Neurotropin, a non-protein extract from the inflamed rabbit skin inoculated with vaccinia virus, has been used to treat various chronic pains. In the present study, we investigated the effect of Neurotropin on the oxaliplatin-induced neuropathy in rats. Repeated administration of oxaliplatin caused cold hyperalgesia from Day 5 to Day 29 and mechanical allodynia from Day 15 to Day 47. Repeated administration of Neurotropin relieved the oxaliplatin-induced mechanical allodynia but not cold hyperalgesia, and inhibited the oxaliplatin-induced axonal degeneration in rat sciatic nerve. Neurotropin also inhibited the oxaliplatin-induced neurite degeneration in cultured pheochromocytoma 12 (PC12) and rat dorsal root ganglion (DRG) cells. On the other hand, Neurotropin did not affect the oxaliplatin-induced cell injury in rat DRG cells. These results suggest that repeated administration of Neurotropin relieves the oxaliplatin-induced mechanical allodynia by inhibiting the axonal degeneration and it is useful for the treatment of oxaliplatin-induced neuropathy clinically.
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Neurotropin reverses paclitaxel-induced neuropathy without affecting anti-tumour efficacy
European Journal of Cancer, 2008Co-Authors: Takehiro Kawashiri, Takao Shimazoe, Takahisa Yano, Yoko Ikegami, Megumu Yoshimura, Nobuaki Egashira, Yoshinori Itoh, Ryozo OishiAbstract:Abstract Paclitaxel is a commonly used anticancer drug, but it frequently causes peripheral neuropathy. Neurotropin, a non-protein extract from inflamed rabbit skin inoculated with vaccinia virus, has been used to treat various chronic painful conditions. In the present study, we investigated the effect of Neurotropin on the paclitaxel-induced neuropathy in rats. Repeated administration of paclitaxel induced mechanical allodynia, cold hyperalgesia, and motor dysfunction. These neuropathies were mostly reversed by the repeated administration of Neurotropin. Furthermore, Neurotropin ameliorated the paclitaxel-induced axonal degeneration in cultured PC12 and rat dorsal root ganglion cells, and in rat sciatic nerve. In addition, Neurotropin did not affect the microtubule aggregation or anti-tumour effect induced by paclitaxel in the tumour cell lines or tumour cells-implanted mice. These results suggest that Neurotropin reverses the paclitaxel-induced neuropathy without affecting anti-tumour activity of paclitaxel, and therefore may be useful for the paclitaxel-induced neuropathy in clinical settings.
Teruaki Nasu - One of the best experts on this subject based on the ideXlab platform.
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a single administration of Neurotropin reduced the elongated immobility time in the forced swimming test of rats exposed to repeated cold stress
Behavioural Pharmacology, 2019Co-Authors: Teruaki Nasu, Asako Kubo, Kazue Mizumura, Luis F QuemeAbstract:: Many people suffer from a major depressive disorder, and chronic pain conditions are often associated with depressive symptoms. Neurotropin, an extract from the inflamed skin of rabbits inoculated with vaccinia virus, has been used for pain relief. Decrease of brain-derived neurotrophic factor (BDNF) in the brain is one of the proposed mechanisms for the major depressive disorders, and Neurotropin has been reported to restore the decreased BDNF in the hippocampus. In this experiment, we examined whether Neurotropin had an antidepressant-like effect in a model of fibromyalgia and whether BDNF in the brain was altered after repeated cold stress (RCS) and Neurotropin treatment. Rats were exposed to RCS because these animals have been used as a model for fibromyalgia syndrome. Depression-like behavior was evaluated using elongation of immobility time in a forced swimming test. Change in expression of BDNF in the brain was also examined by western blot analysis of several brain areas. Depression-like behavior in the forced swimming test was significantly increased 10-14 days after RCS, and this increase was reversed by a single injection of an antidepressant, imipramine, but not by PBS. Increased depression-like behavior was also dose-dependently suppressed by a single administration of Neurotropin (50-200 NU/kg, subcutaneously). BDNF expression was not changed in the brain areas examined (hippocampus, amygdala, prefrontal cortex, and striatum) either after RCS or by Neurotropin injected after RCS. These results suggest that RCS induced a depression-like state in rats, and Neurotropin reversed this state. However, we did not observe a BDNF-related mechanism for these effects.
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Intramuscularly injected Neurotropin reduced muscular mechanical hyperalgesia induced by repeated cold stress in rats.
Behavioural pharmacology, 2018Co-Authors: Teruaki Nasu, Shiori Murase, Yoshiko Takeda-uchimura, Kazue MizumuraAbstract:An extract of rabbit skin inflamed by inoculation with the vaccinia virus, Neurotropin [by intravenous, oral, and intramuscular (i.m.) administration], has been used in China and Japan for the treatment of chronic pain. In this study, we investigated the analgesic mechanism of i.m. Neurotropin. Rats were exposed to repeated cold stress, and muscular mechanical hyperalgesia was evaluated by measuring the withdrawal threshold of the gastrocnemius muscle using Randall-Selitto apparatus. I.m. but not subcutaneous, Neurotropin dose dependently reduced the repeated cold stress-induced muscular mechanical hyperalgesia for 3 h, but it had no effect in normal rats. Injections of Neurotropin into the right gastrocnemius, quadriceps femoris, biceps brachii, and trapezius muscles reduced the muscular mechanical hyperalgesia of the gastrocnemius muscle bilaterally. Intrathecal administration of antagonists to GABAergic, serotonergic, and cholinergic receptors, but not α2-adrenergic receptors, and intraperitoneal administration of opioid receptor antagonist inhibited the analgesic effect of Neurotropin. These results indicated that an i.m. injection of Neurotropin induced long-lasting wide-spread bilateral muscular analgesia by activating spinal serotonergic and GABAergic receptors. As distinct from analgesia by systemic administration, spinal cholinergic and opioidergic, but not adrenergic receptors, are also involved. The present study supports the effectiveness of Neurotropin treatment for muscular mechanical hyperalgesia.