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Differential roles of galanin on mechanical and cooling responses at the primary afferent nociceptor
Richard P Hulse, Lucy F Donaldson, David Wynick
Molecular Pain , 2012, DOI: 10.1186/1744-8069-8-41
Abstract: Mechanically evoked responses in C-fibre nociceptors from naive rats were sensitised after close intra-arterial infusion of galanin or Gal2-11 (a galanin receptor-2/3 agonist) confirming previous data that galanin modulates nociception via activation of GalR2. In contrast, the same dose and route of administration of galanin, but not Gal2-11, inhibited acetone and menthol cooling evoked responses, demonstrating that this inhibitory mechanism is not mediated by activation of GalR2. We then used the partial saphenous nerve ligation injury model of neuropathic pain (PSNI) and the complete Freund’s adjuvant model of inflammation in the rat and demonstrated that close intra-arterial infusion of galanin, but not Gal2-11, reduced cooling evoked nociceptor activity and cooling allodynia in both paradigms, whilst galanin and Gal2-11 both decreased mechanical activation thresholds. A previously described transgenic mouse line which inducibly over-expresses galanin (Gal-OE) after nerve injury was then used to investigate whether manipulating the levels of endogenous galanin also modulates cooling evoked nociceptive behaviours after PSNI. Acetone withdrawal behaviours in naive mice showed no differences between Gal-OE and wildtype (WT) mice. 7-days after PSNI Gal-OE mice demonstrated a significant reduction in the duration of acetone-induced nociceptive behaviours compared to WT mice.These data identify a novel galaninergic mechanism that inhibits cooling evoked neuronal activity and nociceptive behaviours via a putative GalR1 mode of action that would also be consistent with a TRP channel-dependent mechanism.
Galanin Protects against Nerve Injury after Shear Stress in Primary Cultured Rat Cortical Neurons  [PDF]
Meili Liu, Wei Song, Ping Li, Yan Huang, Xianghui Gong, Gang Zhou, Xiaoling Jia, Lisha Zheng, Yubo Fan
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063473
Abstract: The neuropeptide galanin and its receptors (GalR) are found to be up-regulated in brains suffering from nerve injury, but the specific role played by galanin remains unclear. This study aimed to explore the neuroprotective role of galanin after shear stress induced nerve injury in the primary cultured cortical neurons of rats. Our results demonstrated that no significant changes in cell death and viability were found after galanin treatment when subjected to a shear stress of 5 dyn/cm2 for 12 h, after increasing magnitude of shear stress to 10 dyn/cm2 for 12 h, cell death was significantly increased, while galanin can inhibit the nerve injury induced by shear stress with 10 dyn/cm2 for 12 h. Moreover, Gal2-11 (an agonist of GalR2/3) could also effectively inhibit shear stress-induced nerve injury of primary cultured cortical neurons in rats. Although GalR2 is involved in the galanin protection mechanism, there was no GalR3 expression in this system. Moreover, galanin increased the excitatory postsynaptic currents (EPSCs), which can effectively inhibit the physiological effects of shear stress. Galanin was also found to inhibit the activation of p53 and Bax, and further reversed the down regulation of Bcl-2 induced by shear stress. Our results strongly demonstrated that galanin plays a neuroprotective role in injured cortical neurons of rats.
Effects of Exogenous Galanin on Neuropathic Pain State and Change of Galanin and Its Receptors in DRG and SDH after Sciatic Nerve-Pinch Injury in Rat  [PDF]
Xiaofeng Xu, Xiangdong Yang, Ping Zhang, Xiuying Chen, Huaxiang Liu, Zhenzhong Li
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0037621
Abstract: A large number of neuroanatomical, neurophysiologic, and neurochemical mechanisms are thought to contribute to the development and maintenance of neuropathic pain. However, mechanisms responsible for neuropathic pain have not been completely delineated. It has been demonstrated that neuropeptide galanin (Gal) is upregulated after injury in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH) where it plays a predominantly antinociceptive role. In the present study, sciatic nerve-pinch injury rat model was used to determine the effects of exogenous Gal on the expression of the Gal and its receptors (GalR1, GalR2) in DRG and SDH, the alterations of pain behavior, nerve conduction velocity (NCV) and morphology of sciatic nerve. The results showed that exogenous Gal had antinociceptive effects in this nerve-pinch injury induced neuropathic pain animal model. It is very interesting that Gal, GalR1 and GalR2 change their expression greatly in DRG and SDH after nerve injury and intrathecal injection of exougenous Gal. Morphological investigation displays a serious damage after nerve-pinch injury and an amendatory regeneration after exogenous Gal treatment. These findings imply that Gal, via activation of GalR1 and/or GalR2, may have neuroprotective effects in reducing neuropathic pain behaviors and improving nerve regeneration after nerve injury.
Localization of substance P, calcitonin gene related peptide and galanin in the nerve fibers of porcine cystic ovaries  [cached]
Anna Koz?owska,Joanna Wojtkiewicz,Mariusz Majewski,Barbara Jana
Folia Histochemica et Cytobiologica , 2012, DOI: 10.5603/14721
Abstract: In a previous study, we showed that both the noradrenergic and cholinergic component of ovarian innervation is markedly changed in porcine cystic ovaries. The present study is aimed at elucidating the distribution pattern of substance P- (SP), calcitonin gene related peptide CGRP- and/or galanin (GAL)-containing nerve fibers within porcine cystic ovaries. The status polycysticus was induced by dexamethasone phosphate disodium salt i.m. injections performed from the 7th until the 21st day of the first studied estrous cycle. During the same period of time, gilts of the control group received saline. All animals were slaughtered on the expected 11th day of the second studied estrous cycle, and their ovaries were collected. When compared to control gonad, a distinct difference in the distribution pattern and the density of SP-, CGRP- and/or GAL-immunoreactive (GAL-IR) nerve fibers was observed. Thus, unlike in the control gonad, SP- and/or CGRP-IR perivascular nerve fibers were found to supply medullar blood vessels of polycystic ovary. Furthermore, the number of GAL-IR nerve fibers contributing to the ground plexus in polycystic ovaries was higher than that observed in the control gonads. Thus, as may be judged from the profound changes in the distribution pattern of differently chemically coded afferent terminals within polycystic gonads, it appears possible that neuropeptides released from these terminals may take part in the etiopathogenesis of this disorder. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 4, pp. 622–630)
Transplantation of Bone Marrow-Derived Mononuclear Cells Improves Mechanical Hyperalgesia, Cold Allodynia and Nerve Function in Diabetic Neuropathy  [PDF]
Keiko Naruse, Jun Sato, Megumi Funakubo, Masaki Hata, Nobuhisa Nakamura, Yasuko Kobayashi, Hideki Kamiya, Taiga Shibata, Masaki Kondo, Tatsuhito Himeno, Tatsuaki Matsubara, Yutaka Oiso, Jiro Nakamura
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027458
Abstract: Relief from painful diabetic neuropathy is an important clinical issue. We have previously shown that the transplantation of cultured endothelial progenitor cells or mesenchymal stem cells ameliorated diabetic neuropathy in rats. In this study, we investigated whether transplantation of freshly isolated bone marrow-derived mononuclear cells (BM-MNCs) alleviates neuropathic pain in the early stage of streptozotocin-induced diabetic rats. Two weeks after STZ injection, BM-MNCs or vehicle saline were injected into the unilateral hind limb muscles. Mechanical hyperalgesia and cold allodynia in SD rats were measured as the number of foot withdrawals to von Frey hair stimulation and acetone application, respectively. Two weeks after the BM-MNC transplantation, sciatic motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), sciatic nerve blood flow (SNBF), mRNA expressions and histology were assessed. The BM-MNC transplantation significantly ameliorated mechanical hyperalgesia and cold allodynia in the BM-MNC-injected side. Furthermore, the slowed MNCV/SNCV and decreased SNBF in diabetic rats were improved in the BM-MNC-injected side. BM-MNC transplantation improved the decreased mRNA expression of NT-3 and number of microvessels in the hind limb muscles. There was no distinct effect of BM-MNC transplantation on the intraepidermal nerve fiber density. These results suggest that autologous transplantation of BM-MNCs could be a novel strategy for the treatment of painful diabetic neuropathy.
Microinfusion of TNFα and its antibody into locus coeruleus modifies nerve injury induced thermal hyperalgesia and mechanical allodynia  [cached]
Kambiz Rohampour,Homa Manaheji,Saeed Semnanian,Hossein Azizi
Physiology and Pharmacology , 2011,
Abstract: Introduction: Glial activation and secretion of cytokines at the spinal level is known as part of chronic pain pathogenesis. Although changes in TNFα at the supraspinal level are reported during chronic pain, its exact role and site of action remain to be elucidated. We investigated the effect of microinfusion of TNFα into the LC in a rat model of neuropathic pain. Methods: Male Wistar rats were cannulated in the LC. The cannula was connected to an Alzet mini-osmotic pump, which was filled by the drug (vehicle, TNFα or TNFα-antibody) and placed subcutaneously behind the neck. Twenty four-48 hours after cannulation, a chronic constriction injury (CCI) surgery was performed on the contralateral sciatic nerve. Hyperalgesia and allodynia symptoms were assessed 2, 4, 6, 8, 10 and 12 days after CCI. Results: Microinfusion of TNFα (100ng/day) into the LC significantly exacerbated the hyperalgesia in rat models of neuropathic pain on days 2 and 8 after CCI. On the other hand, microinfusion of TNFα antibody (250ng/day) decreased the symptoms of hyperalgesia on days 2, 4, 6, 8, 10 and 14. TNFα antibody also significantly alleviated the CCIinduced allodynia. Conclusion: These data suggest that alterations of TNFα levels in the LC play a crucial role in the development and maintenance of neuropathic pain.
Prevention of Paclitaxel-induced allodynia by Minocycline: Effect on loss of peripheral nerve fibers and infiltration of macrophages in rats
Cui-Cui Liu, Ning Lu, Yu Cui, Tao Yang, Zhi-Qi Zhao, Wen-Jun Xin, Xian-Guo Liu
Molecular Pain , 2010, DOI: 10.1186/1744-8069-6-76
Abstract: Here, we investigate by immunohistochemistry the change of intraepidermal nerve fiber (IENF) in the hind paw glabrous skin, expression of macrophage and activating transcription factor 3 (ATF3) in DRG at different time points after moderate-dose paclitaxel treatment (cumulative dose 24 mg/kg; 3 × 8 mg/kg) in rats. Moreover, we observe the effect of minocycline on the IENF, macrophages and ATF3. The results showed that moderate-dose paclitaxel induced a persisted, gradual mechanical allodynia, which was accompanied by the loss of IENF in the hind paw glabrous skin and up-regulation of macrophages and ATF3 in DRG in rats. The expressions of ATF3 mainly focus on the NF200-positive cells. More importantly, we observed that pretreatment of minocycline at dose of 30 mg/kg or 50 mg/kg, but not 5 mg/kg, prevented paclitaxel-evoked allodynia. The evidence from immunohistochemistry showed that 30 mg/kg minocycline rescued the degeneration of IENF, attenuated infiltration of macrophages and up-regulation of ATF3 induced by paclitaxel treatment in rats.Minocycline prevents paclitaxel-evoked allodynia, likely due to its inhibition on loss of IENF, infiltration of macrophages and up-regulation of ATF3 in rats. The finding might provide potential target for preventing paclitaxel-induced neuropathic pain.Clinical and animal research have shown that paclitaxel, a widely used chemotherapeutic agent against solid tumors, can induce a dose-dependent peripheral sensory neuropathy [1,2]. Subjects following application of paclitaxel mainly experience tingling and allodynia that often occur in a "glove and stocking" distribution [3]. The anti-tumor action of paclitaxel was due to their binding toβ-tubulin of microtubules. It has been thought that such binding impaired axoplasmic transport, thereby leading to a progressive, dying-back axonopathy [4]. Moreover, Siau et al reported that application of low-dose paclitaxel (2 mg/kg) induced the loss of intraepidermal nerve fibers (IENF) on day
Peripheral Galanin Receptor 2 as a Target for the Modulation of Pain  [PDF]
Richard P. Hulse,Lucy F. Donaldson,David Wynick
Pain Research and Treatment , 2012, DOI: 10.1155/2012/545386
Abstract: The neuropeptide galanin is widely expressed in the nervous system and has an important role in nociception. It has been shown that galanin can facilitate and inhibit nociception in a dose-dependent manner, principally through the central nervous system, with enhanced antinociceptive actions after nerve injury. However, following nerve injury, expression of galanin within the peripheral nervous system is dramatically increased up to 120-fold. Despite this striking increase in the peripheral nervous system, few studies have investigated the role that galanin plays in modulating nociception at the primary afferent nociceptor. Here, we summarise the recent work supporting the role of peripherally expressed galanin with particular reference to the dual actions of the galanin receptor 2 in neuropathic pain highlighting this as a potential target analgesic. 1. Introduction The 29-amino-acid neuropeptide galanin was first identified in porcine intestine [1] and later in the rat central nervous system and intestine [2]. Since then galanin has been shown to play important roles in a number of physiological processes including cognition [3], feeding [4], and nociception [5]. This paper will consider activation of galanin receptors on primary afferent nociceptors as a possible target for pain treatment. 2. Galanin-Historical Perspectives and Spinal Nociceptive Processing Galanin is expressed in many areas of the nervous system involved in somatosensation including the dorsal root ganglia (DRG) and spinal cord [6, 7], and also in other CNS regions such as the arcuate nucleus and periaqueductal grey [8, 9]. In the peripheral nervous system, low levels of galanin expression is present in the DRG of intact adult rodents, with the peptide expressed in fewer than 5% of DRG sensory neurons [10]. These galanin-expressing neurons belong to a group of small diameter sensory afferents that respond to capsaicin [7, 11], which are characteristically C fibre nociceptors [12]. Galanin is now considered to be an injury-response peptide, as it is dramatically upregulated in DRG neurons in sciatic [6, 10] and saphenous nerve injury models [13–17]. The original observations of galanin upregulation after peripheral nerve injury strongly suggested a functional role for galanin in nociception and that these actions were through modulation of spinal nociceptive processing. Prior to the identification and characterization of galanin receptors in the central nervous system, functional studies demonstrated that galanin could modulate spinal nociceptive reflexes. Behaviourally, intrathecal
Inhibition of Ca2+/Calmodulin-dependent protein kinase II reverses oxaliplatin-induced mechanical allodynia in Rats
Masafumi Shirahama, Soichiro Ushio, Nobuaki Egashira, Shota Yamamoto, Hikaru Sada, Ken Masuguchi, Takehiro Kawashiri, Ryozo Oishi
Molecular Pain , 2012, DOI: 10.1186/1744-8069-8-26
Abstract: An increase of CaMKII phosphorylation was found in the spinal cord (L4-6) of oxaliplatin-treated rats. This increased CaMKII phosphorylation was reversed by intrathecal injection of a selective CaMKII inhibitor KN-93 (50 nmol, i.t.) and a selective NR2B antagonist Ro 25-6981 (300 nmol, i.t.). Moreover, acute administration of KN-93 (50 nmol, i.t.) strongly reversed the oxaliplatin-induced mechanical allodynia in von Frey test, while it did not affect the oxaliplatin-induced cold hyperalgesia in acetone test. Similarly, oral administration of trifluoperazine (0.1 and 0.3 mg/kg, p.o.), which is an antipsychotic drug and inhibits calmodulin, reduced both mechanical allodynia and increased CaMKII phosphorylation. On the other hand, trifluoperazine at the effective dose (0.3 mg/kg) had no effect on the paw withdrawal threshold in intact rats. In addition, trifluoperazine at the same dose did not affect the motor coordination in rota-rod test in intact and oxaliplatin-treated rats.These results suggest that CaMKII is involved in the oxaliplatin-induced mechanical allodynia, and trifluoperazine may be useful for the treatment of oxaliplatin-induced peripheral neuropathy in clinical setting.Oxaliplatin, a platinum-based chemotherapeutic agent, has widely been used for colorectal cancer. However, oxaliplatin causes severe peripheral neuropathy. After multiple cycles, the patients develop a chronic neuropathy that is characterized by a sensory and motor dysfunction. This chronic neuropathy is a dose-limiting toxicity and a major clinical problem in oxaliplatin-based chemotherapy [1].We previously reported that repeated administration of oxaliplatin induced cold hyperalgesia in the early phase and mechanical allodynia in the late phase in rats [2]. Recently, we reported that spinal NR2B-containing N-methyl-D-aspartate (NMDA) receptors are involved in the oxaliplatin-induced mechanical allodynia [3]. The NMDA receptor antagonists (MK-801 and memantine) and selective NR2B antago
Nerve injury induces robust allodynia and ectopic discharges in Nav1.3 null mutant mice
Mohammed A Nassar, Mark D Baker, Alessandra Levato, Rachel Ingram, Giovanna Mallucci, Stephen B McMahon, John N Wood
Molecular Pain , 2006, DOI: 10.1186/1744-8069-2-33
Abstract: Here we show that acute and inflammatory pain behaviour is unchanged in global Nav1.3 mutant mice. Surprisingly, neuropathic pain also developed normally in the Nav1.3 mutant mouse. To rule out any genetic compensation mechanisms that may have masked the phenotype, we investigated neuropathic pain in two conditional Nav1.3 mutant mouse lines. We used Nav1.8-Cre mice to delete Nav1.3 in nociceptors at E14 and NFH-Cre mice to delete Nav1.3 throughout the nervous system postnatally. Again normal levels of neuropathic pain developed after nerve injury in both lines. Furthermore, ectopic discharges from damaged nerves were unaffected by the absence of Nav1.3 in global knock-out mice. Our data demonstrate that Nav1.3 is neither necessary nor sufficient for the development of nerve-injury related pain.Neuropathic pain is an important and unmet clinical problem. There is a lack of effective drugs for its treatment and in some cases the pain is resistant to the strongest analgesics [1]. Hyperexcitability of damaged sensory neurons, as a result of injury to and/or demyelination of their peripheral axons, is thought to initiate the processes that lead to most neuropathic pain [2,3]. Hyper-excitable neurons can fire spontaneously, causing spontaneous pain, or become hypersensitive to otherwise innocuous mechanical and thermal stimuli giving rise to allodynia (noxious responses to innocuous stimuli) and hyperalgesia (increased perception of noxious stimuli) [2,3].Injured sensory neurons undergo major changes in gene expression that have been catalogued in microarray studies [4-6]. Altered expression of voltage-gated sodium channels (VGSC), which underlie the electrical excitability of nerve and muscle, has been extensively studied [7]. Ectopic activity in damaged neurons [8] and neuropathic pain behavior [9] have been shown to be sensitive to the VGSC blocker, Tetrodotoxin (TTX). Sensory neurons express multiple subtypes of TTX-sensitive and TTX-resistant VGSCs [10]. The express
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