Protopanaxadiol alleviates neuropathic pain by spinal microglial dynorphin A expression following glucocorticoid receptor activation

2021 ◽  
Author(s):  
Rana Muhammad Shoaib ◽  
Khalil Ali Ahmad ◽  
Yong‐Xiang Wang
Keyword(s):  
Neuropathic Pain ◽  
Glucocorticoid Receptor ◽  
Receptor Activation ◽  
Dynorphin A

CB2/miR-124 signaling down-regulate the expression of purinergic P2X4 and P2X7 receptor in dorsal spinal cord of CCI rats

2020 ◽  
Author(s):  
Rui Xu ◽  
Fan Yang ◽  
Lijuan Li ◽  
Xiaohong Liu ◽  
Xiaolu Lei ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Nerve Injury ◽  
Intrathecal Injection ◽  
Receptor Activation ◽  
Cb2 Receptor ◽  
Dorsal Spinal Cord ◽  
P38mapk Pathway ◽  
Dorsal Spinal

Abstract Background: The importance of P2X purinoceptors, CB2 receptor and microRNA-124(miR-124) in spinal cord microglia to the development of neuropathic pain was demonstrated in numerous previous studies. The upregulation of P2X4 and P2X7 receptors in spinal dorsal horn microglia is involved in the development of pain behavior caused by peripheral nerve injury. However, it is not clear whether the expression of P2X4 and P2X7 receptors at dorsal spinal cord will be influenced by CB2 receptor or miR-124 in rats after chronic sciatic nerve injury.Methods: Chronic constriction injury (CCI) of the sciatic nerve was performed in rats to induce neuropathic pain. Tests of the mechanical withdrawal threshold (MWT) were carried out to assess the response of the paw to mechanical stimulus. The expression of miR-124, P2X4, P2X7 and CB2 receptor were detected with RT-PCR. The protein expression of P2X4, P2X7 and CB2 receptor, RhoA, ROCK1, ROCK2, p-p38MAPK and p-NF-kappaBp65 was detected with Western blotting analysis. Results: Intrathecal administration of CB2 receptor agonist AM1241 significantly attenuated CCI-induced mechanical allodynia and significantly inhibited the increased expression of P2X4 and P2X7 receptors at the mRNA and protein levels, which imply that P2X4 and P2X7 receptors expression are down-regulated by AM1241 in CCI rats. Western blot analysis showed that AM1241 suppressed the elevated expression of RhoA, ROCK1, ROCK2, p-p38MAPK and NF-κBp65 in the dorsal spinal cord induced by CCI. After administration with Y-27632 (ROCK inhibitor), SB203580 (P38MAPK inhibitor) or PDTC (NF-κB inhibitor), the levels of P2X4 and P2X7 receptors expression in the dorsal spinal cord were lower than those in CCI rats, which imply that the ROCK/P38MAPK pathway and NF-κB activation may contribute to the increased expression of P2X4 and P2X7 receptor. On the other hand, in CCI rats, AM1241 treatment evoked the increased expression of CB2 receptor and miRNA-124, which can be inhibited by intrathecal injection of CB2 receptor antagonist AM630, which indicate that the increased expression of miRNA-124 may be medicated by CB2 receptor activation. In addition, the increased expression of P2X4 and P2X7 receptors in the dorsal spinal cord of CCI rats were inhibited by miRNA-124 agomir. Furthermore, intrathecal injection of miRNA-124 agomir could efficiently inhibit the ROCK/P38MAPK pathway and NF-κB activation in CCI rats. Moreover, AM1241 treatment significantly inhibited the expression of P2X4 and P2X7 receptors, and this suppression is enhanced by pretreatment with miRNA-124 agomir. On the contrast, the inhibitory effect of AM1241 on the expression of P2X4 and P2X7 receptor can be reversed by pretreatment with miRNA-124 antagomir.Conclusions: In CCI rats, intrathecal injection of AM1241 could efficiently induce the increased expression of miRNA-124, while inhibiting the ROCK/P38MAPK pathway and NF-κB activation in dorsal spinal cord. CB2 receptor/miRNA-124 signaling induced the decreased P2X4 and P2X7 receptors expression via inhibit the ROCK/P38MAPK pathway and NF-κB activation.

Dynorphin A Elicits an Increase in Intracellular Calcium in Cultured Neurons Via a Non-Opioid, Non-NMDA Mechanism

2000 ◽  
Vol 83 (5) ◽  
pp. 2610-2615 ◽  
Author(s):  
Qingbo Tang ◽  
Ronald M. Lynch ◽  
Frank Porreca ◽  
Josephine Lai
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Intracellular Calcium ◽  
Cortical Neurons ◽  
Excitatory Amino Acid ◽  
Receptor Activation ◽  
Dependent Manner ◽  
Dynorphin A ◽  
Excitatory Effect

The opioid peptide dynorphin A is known to elicit a number of pathological effects that may result from neuronal excitotoxicity. An up-regulation of this peptide has also been causally related to the dysesthesia associated with inflammation and nerve injury. These effects of dynorphin A are not mediated through opioid receptor activation but can be effectively blocked by pretreatment with N-methyl-d-aspartate (NMDA) receptor antagonists, thus implicating the excitatory amino acid system as a mediator of the actions of dynorphin A and/or its fragments. A direct interaction between dynorphin A and the NMDA receptors has been well established; however the physiological relevance of this interaction remains equivocal. This study examined whether dynorphin A elicits a neuronal excitatory effect that may underlie its activation of the NMDA receptors. Calcium imaging of individual cultured cortical neurons showed that the nonopioid peptide dynorphin A(2-17) induced a time- and dose-dependent increase in intracellular calcium. This excitatory effect of dynorphin A(2-17) was insensitive to (+)-5-methyl-10,11-dihydro-5 H-dibenzo[ a,d]-cyclohepten-5,10-imine (MK-801) pretreatment in NMDA-responsive cells. Thus dynorphin A stimulates neuronal cells via a nonopioid, non-NMDA mechanism. This excitatory action of dynorphin A could modulate NMDA receptor activity in vivo by enhancing excitatory neurotransmitter release or by potentiating NMDA receptor function in a calcium-dependent manner. Further characterization of this novel site of action of dynorphin A may provide new insight into the underlying mechanisms of dynorphin excitotoxicity and its pathological role in neuropathy.

Glucocorticoid receptor activation in isolated perfused rat hearts

1989 ◽  
Vol 256 (2) ◽  
pp. C219-C225 ◽  
Author(s):  
S. M. Czerwinski ◽  
E. E. McKee ◽  
R. C. Hickson
Keyword(s):  
Glucocorticoid Receptor ◽  
Triamcinolone Acetonide ◽  
Deae Cellulose ◽  
Potassium Phosphate ◽  
Receptor Activation ◽  
Receptor Complexes ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Cellulose Binding ◽  
Isolated Perfused Rat Hearts

The formation of unactivated and activated glucocorticoid receptor complexes was studied in intact, isolated, perfused rat hearts in the presence of [3H]triamcinolone acetonide. Receptor activation, as quantified by the DNA-cellulose-binding assay, began to increase within 30 s of perfusion and reached a final steady-state level (t 1/2 = 4.6 min) with 46% of the steroid-receptor complexes bound to DNA-cellulose. With the use of a linear potassium phosphate (KP) gradient (5-400 mM), unactivated receptors eluted from DEAE-cellulose anion exchange columns at approximately 250 mM KP. Two activated receptor forms appeared, which eluted either in the wash fraction (binder IB) or between 50 and 100 mM KP (binder II) and occurred with half times of 1.3 and 2.7 min, respectively. Postperfusion cytosol preparation did not markedly influence the results as receptor binding was reduced by 10% or less when a 100-fold excess of unlabeled triamcinolone acetonide was included in the homogenizing buffer. We conclude from these results that glucocorticoids are able to exert a direct effect on the heart through binding to their own receptor in the absence of endogenous hormones. The time dependency of receptor activation supports a physiological role for this process. However, activation rates, determined from conformational changes associated with altered DEAE-cellulose elution profiles and appearance of activated receptor forms, occur earlier and may not be coordinated with the rate of activation as quantified by DNA-cellulose binding.

scholarly journals Glucocorticoid Receptor Activation of theCiz1-Lcn2Locus by Long Range Interactions

2009 ◽  
Vol 284 (10) ◽  
pp. 6048-6052 ◽  
Author(s):  
Ofir Hakim ◽  
Sam John ◽  
Jian Qun Ling ◽  
Simon C. Biddie ◽  
Andrew R. Hoffman ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Long Range ◽  
Receptor Activation ◽  
Long Range Interactions

Redefinition of modulator as an inhibitor of glucocorticoid receptor activation

1981 ◽  
Vol 14 (2) ◽  
pp. 161-166 ◽  
Author(s):  
Bernard C. Sekula ◽  
Thomas J. Schmidt ◽  
Gerald Litwack
Keyword(s):  
Glucocorticoid Receptor ◽  
Receptor Activation
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