scholarly journals Inhibition of the phosphoinositide 3-kinase-AKT-cyclic GMP-c-Jun N-terminal kinase signaling pathway attenuates the development of morphine tolerance in a mouse model of neuropathic pain

2021 ◽  
Vol 17 ◽  
pp. 174480692110033
Author(s):  
Travis Okerman ◽  
Taylor Jurgenson ◽  
Madelyn Moore ◽  
Amanda H Klein
Keyword(s):  
Spinal Cord ◽  
Sciatic Nerve ◽  
Signaling Pathway ◽  
Intracellular Signaling ◽  
Morphine Tolerance ◽  
Spinal Nerve ◽  
Intracellular Signaling Pathway ◽  
Spinal Cord Dorsal ◽  
Phosphoinositide 3 Kinase ◽  
Induced Tolerance

Research presented here sought to determine if opioid induced tolerance is linked to activity changes within the PI3Kγ-AKT-cGMP-JNK intracellular signaling pathway in spinal cord or peripheral nervous systems. Morphine or saline injections were given subcutaneously twice a day for five days (15 mg/kg) to male C57Bl/6 mice. A separate cohort of mice received spinal nerve ligation (SNL) one week prior to the start of morphine tolerance. Afterwards, spinal cord, dorsal root ganglia, and sciatic nerves were isolated for quantifying total and phosphorylated- JNK levels, cGMP, and gene expression analysis of Pik3cg, Akt1, Pten, and nNos1. This pathway was downregulated in the spinal cord with increased expression in the sciatic nerve of morphine tolerant and morphine tolerant mice after SNL. We also observed a significant increase in phosphorylated- JNK levels in the sciatic nerve of morphine tolerant mice with SNL. Pharmacological inhibition of PI3K or JNK, using thalidomide, quercetin, or SP600125, attenuated the development of morphine tolerance in mice with SNL as measured by thermal paw withdrawal. Overall, the PI3K/AKT intracellular signaling pathway is a potential target for reducing the development of morphine tolerance in the peripheral nervous system. Continued research into this pathway will contribute to the development of new analgesic drug therapies.

scholarly journals Inhibition of the phosphoinositide 3-kinase-AKT-cyclic GMP-c-Jun N-terminal kinase signaling pathway attenuates the development of morphine tolerance in a mouse model of neuropathic pain

2020 ◽  
Author(s):  
T. Okerman ◽  
T. Jurgenson ◽  
M. Moore ◽  
A. H. Klein
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Sciatic Nerve ◽  
Signaling Pathway ◽  
Dorsal Root Ganglia ◽  
Intracellular Signaling ◽  
Dorsal Root ◽  
Morphine Tolerance ◽  
Spinal Nerve ◽  
Intracellular Signaling Pathway

AbstractBackgroundOpioid management of chronic pain can cause opioid-induced analgesic tolerance and hyperalgesia, complicating clinical pain-management treatments. Research presented here sought to determine if opioid induced tolerance is linked to activity changes within the PI3Kγ-AKT-cGMP-JNK intracellular signaling pathway in spinal cord or peripheral nervous systems.MethodsMorphine or saline injections were given subcutaneously twice a day for five days (15 mg/kg) to male C57Bl6 mice. A separate cohort of mice received spinal nerve ligation (SNL) one week prior to the start of morphine tolerance. Afterwards, spinal cord, dorsal root ganglia, and sciatic nerves were isolated for quantifying total and phosphorylated-JNK levels, cGMP, and gene expression analysis.ResultsGene expression for the PI3Kγ-AKT-cGMP-JNK signaling pathway including, Akt1, Akt2, Akt3, Pik3cg, Pten, Jnk3, and nNos1 were decreased in the spinal cord with varied expression changes in the dorsal root ganglia and sciatic nerve of morphine tolerant and morphine tolerant mice after SNL. We observed significant increases in total and phosphorylated-JNK levels in the spinal cord, total JNK in dorsal root ganglia, and cGMP in the sciatic nerve of morphine tolerant mice with SNL. Pharmacological inhibition of PI3K, nNOS, or JNK, using thalidomide, quercetin, or SP600125, attenuated the development of morphine tolerance in mice with SNL as measured by thermal paw withdrawal.ConclusionsOverall, the PI3K/AKT intracellular signaling pathway is a potential target for reducing the development of morphine tolerance. Continued research into this pathway will contribute to the development of new analgesic drug therapies.

scholarly journals Effect of Testosterone on Intracellular Signaling Pathway of Angiogenesis in Sciatic Nerve of Male Diabetic Rats

2015 ◽  
Vol 8 (2) ◽  
pp. 823-829 ◽  
Author(s):  
SONABARKABI ZANJANI ◽  
FARIBAMIRZAEI BAVIL ◽  
MOSTAFA MOHAMMADI ◽  
LEILA CHODADI ◽  
MEHRANMESGARI ABBASI ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Signaling Pathway ◽  
Intracellular Signaling ◽  
Diabetic Rats ◽  
Intracellular Signaling Pathway

227 PHOSPHOINOSITIDE-3-KINASE SIGNALING AND THE CONTROL OF SPERM MOTILITY IN THE PORCINE OVIDUCT

2008 ◽  
Vol 20 (1) ◽  
pp. 193 ◽  
Author(s):  
N. Satake ◽  
P. F. Watson ◽  
W. V. Holt
Keyword(s):  
Signaling Pathway ◽  
Sperm Motility ◽  
Intracellular Signaling ◽  
Physiological State ◽  
Apical Plasma Membrane ◽  
Mitochondrial Activity ◽  
Intracellular Signaling Pathway ◽  
Pi3k Inhibitors ◽  
Phosphoinositide 3 Kinase ◽  
Boar Spermatozoa

Prior to ovulation, interactions of spermatozoa with the oviductal epithelium lead to the formation of a sperm reservoir; here we investigate the hypothesis that the physiological state of the stored spermatozoa is modulated by the epithelial cells. In the pig, where modulation of sperm motility is sensitive to environmental components, the high bicarbonate content of the oviductal fluid would be expected to stimulate motility to its maximal extent; however, as this is incompatible with reservoir formation, we postulate that a signaling pathway counteracts bicarbonate stimulation and depresses motility (Satake et al. 2006 J. Exp. Biol. 209, 1560–1572). We chose to investigate a signaling mechanism which may suppress sperm motility through phosphoinositide-3-kinase (PI3K). Boar spermatozoa were exposed to solubilized proteins derived from the oviduct epithelial apical plasma membrane (sAPM). We exploited the motility activation effects of bicarbonate on Percoll-washed boar spermatozoa to see whether it was countered by sAPM and reversed by PI3K inhibitors. Washed spermatozoa (n = 9 boars) were incubated (10 min at 38�C) in Tyrode's medium in the presence of sAPM (25 and 50 µg mL–1) or PI3K inhibitors (LY294002 or wortmannin) prior to activation with 15 mm bicarbonate/CO2, and then incubated for a further 35 min. Sperm motility was monitored at 5-min intervals using a Hobson Sperm Tracker (Hobson Tracker, Ltd., Sheffield, UK). Samples were also analyzed with a flow cytometer for mitochondrial activity using JC-1. PATN analysis (Belbin 1993 PATN Pattern Analysis Package, Div. Wildlife & Ecol., CSIRO, Canberra, Australia) was used to distinguish four motility-based sperm subgroups within the data. The proportions of fast and progressive spermatozoa showed significant and rapid (<5 min) bicarbonate-induced increases when there was no sAPM treatment, or when PI3K inhibitors were present. However, there was no significant bicarbonate-induced increase in the presence of sAPM alone, or when spermatozoa were exposed to a mixture of wortmannin and sAPM. PI3K inhibition by LY294002 reversed the sAPM-induced motility suppression (P < 0.001). Mitochondrial membrane potential was also suppressed by sAPM and restored by the presence of LY294002 (P < 0.01). These results support the hypothesis that the sperm–oviduct interaction is modulated by an intracellular signaling pathway involving PI3K and appropriate receptors.

scholarly journals Intracellular Signaling Pathway Activation via TGF-β Differs in the Anterior and Posterior Axis During Palatal Development

2016 ◽  
Vol 25 (2) ◽  
pp. 195-204
Author(s):  
Arisa Higa ◽  
Kyoko Oka ◽  
Michiko Kira-Tatsuoka ◽  
Shougo Tamura ◽  
Satoshi Itaya ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Intracellular Signaling ◽  
Intracellular Signaling Pathway ◽  
Pathway Activation ◽  
Palatal Development

scholarly journals Insulin-stimulated GLUT4 Translocation Is Mediated by a Divergent Intracellular Signaling Pathway

1995 ◽  
Vol 270 (47) ◽  
pp. 27991-27994 ◽  
Author(s):  
Tetsuro Haruta ◽  
Aaron J. Morris ◽  
David W. Rose ◽  
James G. Nelson ◽  
Michael Mueckler ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Intracellular Signaling ◽  
Glut4 Translocation ◽  
Intracellular Signaling Pathway

scholarly journals Intracellular signaling pathway to prevent caspase activation in osteoclasts.

1999 ◽  
Vol 79 ◽  
pp. 278
Author(s):  
Mitsue Shibata ◽  
Kazuhiro Kanaoka ◽  
Yasuhiro Kobayashi ◽  
Yuzo Kato ◽  
Hideaki Sakai
Keyword(s):  
Signaling Pathway ◽  
Intracellular Signaling ◽  
Caspase Activation ◽  
Intracellular Signaling Pathway

scholarly journals Mel1c Mediated Monochromatic Light-Stimulated IGF-I Synthesis through the Intracellular Gαq/PKC/ERK Signaling Pathway

2019 ◽  
Vol 20 (7) ◽  
pp. 1682
Author(s):  
Shujie Ning ◽  
Zixu Wang ◽  
Jing Cao ◽  
Yulan Dong ◽  
Yaoxing Chen
Keyword(s):  
Signaling Pathway ◽  
Intracellular Signaling ◽  
Monochromatic Light ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Erk Signaling ◽  
Sham Operation ◽  
Intracellular Signaling Pathway ◽  
Igf I

Previous studies have demonstrated that monochromatic light affects plasma melatonin (MEL) levels, which in turn regulates hepatic insulin-like growth factor I (IGF-I) secretion via the Mel1c receptor. However, the intracellular signaling pathway initiated by Mel1c remains unclear. In this study, newly hatched broilers, including intact, sham operation, and pinealectomy groups, were exposed to either white (WL), red (RL), green (GL), or blue (BL) light for 14 days. Experiments in vivo showed that GL significantly promoted plasma MEL formation, which was accompanied by an increase in the MEL receptor, Mel1c, as well as phosphorylated extracellular regulated protein kinases (p-ERK1/2), and IGF-I expression in the liver, compared to the other light-treated groups. In contrast, this GL stimulation was attenuated by pinealectomy. Exogenous MEL elevated the hepatocellular IGF-I level, which is consistent with increases in cyclic adenosine monophosphate (cAMP), Gαq, phosphorylated protein kinase C (p-PKC), and p-ERK1/2 expression. However, the Mel1c selective antagonist prazosin suppressed the MEL-induced expression of IGF-I, Gαq, p-PKC, and p-ERK1/2, while the cAMP concentration was barely affected. In addition, pretreatment with Ym254890 (a Gαq inhibitor), Go9863 (a PKC inhibitor), and PD98059 (an ERK1/2 inhibitor) markedly attenuated MEL-stimulated IGF-I expression and p-ERK1/2 activity. These results indicate that Mel1c mediates monochromatic GL-stimulated IGF-I synthesis through intracellular Gαq/PKC/ERK signaling.

scholarly journals Akt Inhibitor Akt-IV Blocks Virus Replication through an Akt-Independent Mechanism

2009 ◽  
Vol 83 (22) ◽  
pp. 11665-11672 ◽  
Author(s):  
Ewan F. Dunn ◽  
Rachel Fearns ◽  
John H. Connor
Keyword(s):  
Signaling Pathway ◽  
Virus Replication ◽  
Intracellular Signaling ◽  
Akt Pathway ◽  
Akt Inhibitor ◽  
Antiviral Compound ◽  
Intracellular Signaling Pathway ◽  
Cytopathic Effects ◽  
Syncytial Virus

ABSTRACT Many viruses activate the phosphatidylinositol 3′-kinase (PI3k)/Akt intracellular signaling pathway to promote viral replication. We have analyzed whether a rapidly replicating rhabdovirus, vesicular stomatitis virus (VSV), requires the PI3k/Akt signaling pathway for its replication. Through the use of chemical inhibitors of PI3k and Akt, we show that VSV replication and cytopathic effects do not require activation of these kinases. Inhibitors that block the activating phosphorylations of Akt at threonine 308 (Thr308) and serine 473 (Ser473) did not inhibit VSV protein expression or the induction of the cytopathic effects of VSV. One compound, Akt inhibitor Akt-IV, inhibited the replication of VSV, respiratory syncytial virus, and vaccinia virus but increased the phosphorylation of Akt at positions Thr308 and Ser473 and did not inhibit Akt kinase activity in vitro. Together, our data suggest that the PI3k/Akt pathway is of limited relevance to the replication of VSV but that Akt inhibitor Akt-IV is a novel broad-spectrum antiviral compound with a mechanism differing from that of its previously reported effect on the PI3k/Akt pathway. Identification of other targets for this compound may define a new approach for blocking virus replication.

Sign in / Sign up

Export Citation Format

Share Document