Involvement of p38 MAPK activation mediated through AT1 receptors on spinal astrocytes and neurons in angiotensin II- and III-induced nociceptive behavior in mice

Nemoto, Wataru; Okita, Yoshiki; Nakagawasai, Osamu; Yaoita, Fukie; Tadano, Takeshi; Tan-No, Koichi

doi:10.1016/j.neuropharm.2015.07.022

Cited by 28 publications

(32 citation statements)

References 53 publications

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“…Intrathecal injections were performed as previously described (Nemoto et al, 2013(Nemoto et al, , 2014(Nemoto et al, , 2015a.…”

Section: Intrathecal Injectionsmentioning

confidence: 99%

“…Immunohistochemical staining was conducted as previously described (Nemoto et al, 2014(Nemoto et al, , 2015a. Immunofluorescence double labeling was achieved by incubating 40-mm-thick slices with the primary antibodies, rabbit anti-ACE antibody, goat anti-ACE antibody, mouse anti-GFAP antibody, mouse anti-NeuN antibody, and/or rabbit anti-Iba-1 antibody, diluted with PBS containing 0.3% Triton-X and 1% NGS or NDS, correspondingly, overnight at 4°C.…”

Section: Immunohistochemical Studymentioning

confidence: 99%

“…Western blotting was conducted as previously described (Nemoto et al, 2013(Nemoto et al, , 2014(Nemoto et al, , 2015a. Electrophoresis was performed in 7.5% acrylamide gels for the detection of ACE; 10% acrylamide gels were used in all other cases.…”

Section: Western Blottingmentioning

confidence: 99%

“…In both rat and human dorsal root ganglia (DRGs) Ang II is colocalized in two known regulators for nociception and sensory transmission: substance P and calcitonin gene-related peptide (Patil et al, 2010). We have previously demonstrated that when mice are administered Ang II intrathecally, p38 mitogenactivated protein kinase (MAPK) is phosphorylated through AT1 receptors, leading to nociceptive behavior (Nemoto et al, 2013(Nemoto et al, , 2015a. Moreover, injections of 2% formalin into mice hind paws increases Ang II approximately 1.5-fold on the ipsilateral side of the lumbar superficial dorsal horn, and AT1 receptor antagonist losartan dose-dependently produces an antinociceptive effect by inhibiting p38 MAPK phosphorylation (Nemoto et al, 2015b).…”

Section: Introductionmentioning

confidence: 99%

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Involvement of Spinal Angiotensin II System in Streptozotocin-Induced Diabetic Neuropathic Pain in Mice

et al. 2016

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Renin-angiotensin system (RAS) activity increases under hyperglycemic states, and is thought to be involved in diabetic complications. We previously demonstrated that angiotensin (Ang) II, a main bioactive component of the RAS, might act as a neurotransmitter and/or neuromodulator in the transmission of nociceptive information in the spinal cord. Here, we examined whether the spinal Ang II system is responsible for diabetic neuropathic pain induced by streptozotocin (STZ). Tactile allodynia was observed concurrently with an increase in blood glucose levels the day after mice received STZ (200 mg/kg, i.v.) injections. Tactile allodynia on day 14 was dose-dependently inhibited by intrathecal administration of losartan, an Ang II type 1 (AT1) receptor antagonist, but not by PD123319, an AT2 receptor antagonist. In the lumbar dorsal spinal cord, the expression of Ang II, Ang converting enzyme (ACE), and phosphop38 mitogen-activated protein kinase (MAPK) were all significantly increased on day 14 after STZ injection compared with vehicletreated controls, whereas no differences were observed among AT1 receptors or angiotensinogen levels. Moreover, the increase in phospho-p38 MAPK was significantly inhibited by intrathecal administration of losartan. These results indicate that the expression of spinal ACE increased in STZ-induced diabetic mice, which in turn led to an increase in Ang II levels and tactile allodynia. This increase in spinal Ang II was accompanied by the phosphorylation of p38 MAPK, which was shown to be mediated by AT1 receptors.

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“…Intrathecal injections were performed as previously described (Nemoto et al, 2013(Nemoto et al, , 2014(Nemoto et al, , 2015a.…”

Section: Intrathecal Injectionsmentioning

confidence: 99%

Section: Immunohistochemical Studymentioning

confidence: 99%

Section: Western Blottingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Involvement of Spinal Angiotensin II System in Streptozotocin-Induced Diabetic Neuropathic Pain in Mice

et al. 2016

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“…Fluorescent double-label immunohistochemistry was carried out using the primary antibody for a neuronal nuclear antigen (NeuN) 27) (1 : 100 dilution; EMD Millipore, Billerica, MA, U.S.A., #MAB377, clone A60), and sections were counterstained with 4′,6-diamidino-2-phenylindole dihydrochloride (DAPI) to stain the nuclei of all cells. The secondary antibodies used were Alexa 488 -conjugated goat-anti rabbit and Alexa 555 -conjugated goat anti-mouse (1 : 750 dilution; Molecular Probes, Eugene, OR, U.S.A.).…”

Section: Fig 2 Experimental Strategiesmentioning

confidence: 99%

The Bisphosphonates Clodronate and Etidronate Exert Analgesic Effects by Acting on Glutamate- and/or ATP-Related Pain Transmission Pathways

Shima

Nemoto

Tsuchiya

et al. 2016

Biological & Pharmaceutical Bulletin

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Key words analgesic effect; clodronate; etidronate; phosphate transporter; ATP; glutamate Bisphosphonates (BPs) are used against various boneresorptive diseases, and the nitrogen-containing BPs (N-BPs) have much more powerful anti-bone-resorptive effects than the non-nitrogen-containing BPs (non-N-BPs) 1) (Fig. 1). However, N-BPs have inflammatory and/or necrotic effects, including fever, musculoskeletal pain, direct injuries to esophageal and gastric tissues, and osteonecrosis of the jaw.2) N-BPs, having entered cells (including osteoclasts), exhibit cytotoxicity due to inhibition of farnesyl pyrophosphate synthase in the mevalonate pathway of cholesterol biosynthesis, 1) reducing the prenylation of various proteins, including small guanosine 5′-triphosphatase (GTPases). 3)In contrast to N-BPs, the non-N-BPs etidronate and clodronate are almost devoid of inflammatory/necrotic effects. 4)Interestingly, they can reduce such side effects of N-BPs in mice. [5][6][7][8] Concerning the mechanisms by which clodronate (Clo) and etidronate (Eti) reduce the inflammatory/necrotic effects of N-BPs, our pharmacological studies have suggested that: (a) N-BPs may enter soft-tissue cells via phosphate transporters of the SLC20 and SLC34 families, (b) Clo and Eti may inhibit those families, possibly by competitive inhibition, and thereby inhibit the entry of N-BPs into soft-tissue cells, and (c) Clo and Eti may also inhibit phosphate transporters of the SLC17 family. 9)Pain is a cause of distress in many patients with osteoporosis. Fujita et al. found that in patients with osteoporosis and/ or osteoarthritis, Eti displayed an analgesic effect that was greater than those of N-BPs. 10) We recently reported that Clo and Eti exhibit analgesic effects in mice, possibly via direct interaction with neurons. 11) However, the mechanism underlying the analgesic effects of Clo and Eti remains unclear.Surprisingly, and very interestingly, the SLC17 family of transporters, initially characterized as phosphate carriers, was recently found to include neuronal vesicular transporters of glutamate and ATP. [12][13][14][15] The N-methyl-D-aspartate (NMDA) receptor (NMDA-R), an ionotropic receptor for glutamate, is distributed within the spinal cord and plays an important role in pain transmission. [16][17][18] In addition, nucleotides are released or leaked from non-excitable cells, as well as neurons, under both physiological and pathophysiological conditions, and recent studies indicate that ATP plays important roles during pain transmission through the ionotropic purinoceptor P2X-R. 19,20) There are as yet no reports describing relationships between BPs and neuronal transmitters. However, on the basis of the findings described above, we hypothesized that Clo and Eti may enter neurons through SLC20 and/or SLC34, and then act on neuronal vesicles to inhibit SLC17 transporter-mediated transport of glutamate and/or ATP (resulting in decrements in the levels of glutamate and ATP within the vesicles) (Fig.

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Anti‐hypersensitive effect of angiotensin (1‐7) on streptozotocin‐induced diabetic neuropathic pain in mice

Okita

Nemoto

Yamagata

et al. 2018

European Journal of Pain

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Background We have recently reported that the spinal angiotensin (Ang) converting enzyme (ACE)/Ang II/AT1 receptor axis and downstream p38 MAPK phosphorylation are activated in streptozotocin (STZ)‐induced diabetic mice and lead to tactile hypersensitivity. Moreover, our previous results suggested that the intrathecal (i.t.) administration of Ang (1‐7), an N‐terminal fragment of Ang II, may attenuate the Ang II‐induced nociceptive behaviour through the inhibition of p38 MAPK phosphorylation via Mas receptors. Here, we investigated whether the i.t. administration of Ang (1‐7) can attenuate STZ‐induced diabetic neuropathic pain. Methods Tactile and thermal hypersensitivities were determined using the von Frey filament and Hargreaves tests, respectively. The protein expression of ACE2, Mas receptors and phospho‐p38 MAPK was measured by western blotting. Spinal ACE2 activity was determined using ACE2 activity assay kit. Results The i.t. administration of Ang (1‐7) significantly reduced the tactile and thermal hypersensitivities on day 14 after STZ injection, and these effects were significantly prevented by the Mas receptor antagonist A779. The expression of ACE2 and Mas receptors in the plasma membrane fraction of the lumbar dorsal spinal cord was both significantly decreased in STZ mice. Spinal ACE2 activity was also decreased while p38 MAPK phosphorylation was increased in the lumbar dorsal region of these mice. This phosphorylation was attenuated by the injection of Ang (1‐7), whose effect was reversed by A779. Conclusions Our data demonstrate that Ang (1‐7) attenuates STZ‐induced diabetic neuropathic pain and that this occurs through a mechanism involving spinal Mas receptors and he inhibition of p38 MAPK phosphorylation. Significance The ACE2/Ang (1‐7)/Mas receptor axis was down‐regulated in the spinal cord of STZ mice and the i.t. administration of Ang (1‐7) attenuated the STZ‐induced diabetic neuropathic pain via Mas receptors. Therefore, the activation of this axis could be an effective therapeutic target to alleviate the neuropathic pain in diabetic patients.

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Involvement of p38 MAPK activation mediated through AT1 receptors on spinal astrocytes and neurons in angiotensin II- and III-induced nociceptive behavior in mice

Cited by 28 publications

References 53 publications

Involvement of Spinal Angiotensin II System in Streptozotocin-Induced Diabetic Neuropathic Pain in Mice

Involvement of Spinal Angiotensin II System in Streptozotocin-Induced Diabetic Neuropathic Pain in Mice

The Bisphosphonates Clodronate and Etidronate Exert Analgesic Effects by Acting on Glutamate- and/or ATP-Related Pain Transmission Pathways

Anti‐hypersensitive effect of angiotensin (1‐7) on streptozotocin‐induced diabetic neuropathic pain in mice

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