A3 receptor agonist modulates IL-1ß hippocampus levels in a rat model of neuropathic pain

Introduction: Considering the lack of specific treatments for neuropathic pain, this study aimed to evaluate the effect of a single dose of adenosine A3 receptor IB-MECA on inflammatory and neurotrophic parameters in rats subjected to a neuropathic pain model. Methods: 64 adult male Wistar rats were used. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve and the treatment consisted of a 0.5 µmol/kg dose of IB-MECA, a selective A3 adenosine receptor agonist, dissolved in 3% DMSO; vehicle groups received DMSO 3% in saline solution, and morphine groups received 5 mg/kg. Cerebral cortex and hippocampus IL-1ß, BDNF, and NGF levels were determined by Enzyme-Linked Immunosorbent assay. Results: The main outcome was that a single dose of IB-MECA was able to modulate the IL-1ß hippocampal levels in neuropathic pain induced by CCI and the DMSO increased IL-1ß and NGF hippocampal levels in sham-operated rats. However, we did not observe this effect when the DMSO was used as vehicle for IB-MECA, indicating that IB-MECA was able to prevent the effect of DMSO. Conclusions: Considering that the IL-1ß role in neuropathic pain and the contributions of the hippocampus are well explored, our result corroborates the relationship between the A3 receptor and the process of chronic pain maintenance.

Amitriptyline inhibits the MAPK/ERK and CREB pathways and proinflammatory cytokines through A3AR activation in rat neuropathic pain models / 대한마취과학회지

BACKGROUND: The pain-relief properties of tricyclic antidepressants can be attributed to several actions. Recent observations suggest that adenosine is involved in the antinociceptive effect of amitriptyline. The A3 adenosine receptor (A3AR) is the only adenosine subtype overexpressed in inflammatory and cancer cells. This study was performed to investigate the role of A3AR in the anti-nociceptive effect of amitriptyline. METHODS: Spinal nerve-ligated neuropathic pain was induced by ligating the L5 and L6 spinal nerves of male Sprague-Dawley rats. The neuropathic rats were randomly assigned to one of the following three groups (8 per group): a neuropathic pain with normal saline group, a neuropathic pain with amitriptyline group, and a neuropathic pain with amitriptyline and 3-ethyl-5-benzyl- 2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS) group. Amitriptyline or saline was administered intraperitoneally and 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191), an A3AR antagonist, was injected subcutaneously immediately before amitriptyline administration. The level of extracellular signal-regulated kinase P44/42 (ERK1/2), cyclic AMP response element-binding protein (CREB), and proinflammatory cytokines were assessed using immunoblotting or reverse-transciption polymerase chain reaction. RESULTS: Amitriptyline increased the mechanical withdrawal threshold of the neuropathic rats. The level of phospho-ERK1/2 and phospho-CREB proteins, and proinflammatory cytokines produced by spinal nerve ligation were significantly reduced by amitriptyline administration. However, the use of MRS-1191 before amitriptyline administration not only reduced the threshold of mechanical allodynia, but also increased the signaling protein and proinflammatory cytokine levels, which were reduced by amitriptyline. CONCLUSIONS: The results of this study suggest that the anti-nociceptive effect of amitriptyline involves the suppression of ERK1/2 and CREB signaling proteins, and A3AR activation also affects the alleviation of the inflammatory response.

Effects of Adenosine and the Selective Adenosine Receptor Agonist on the Expression of Interleukin-18 in Patient with Unstable Angina / 天津医药

Objective To observe the effects of adenosine and adenosine receptor agonist on the expression of inter?leukin-18 (IL-18) in patients with unstable angina (UAP), and the mechanism of adenosine receptor agonists thereof. Meth?ods Fifteen UAP and 15 healthy volunteers were included in this study. The effects of adenosine and the selective adenos?ine receptor agonists on the expression of IL-18 were measured by enzyme-linked immunosorbent assay (ELISA). Results The lower concentration of adenosine (1-100μmol/L) increased the expression of IL-18 in UAP group;whereas the higher concentration of adenosine (1 mmol/L) inhibited the expression of IL-18. The adenosine A1 receptor agonist and A3 receptor agonist increased the expression of IL-18, while the adenosine A2a receptor agonist inhibited the expression of IL-18. There was no significant effect for A2b receptor agonist on the expression of IL-18. Conclusion The lower concentrations of ade?nosine can enhance the expression of IL-18 through adenosine A1 and A3 receptors in UAP. The higher concentrations of ade?nosine can inhibit the expression of IL-18 through adenosine A2a receptors. Adenosine can promote IL-18 expression in lower concentrations.

Role of A_3 adenosine receptor on vascular reactivity of superior mesenteric artery in hemorrhagic shock in rat / 中国病理生理杂志

AIM:To explore whether A3 adenosine receptor plays a role in the modulation of vascular reactivity after hemorrhagic shock in rat,and to find out the prospective drug target to restore the decreased vascular reactivity following hemorrhagic shock. METHODS:The hemorrhagic shock (40 mmHg) model was established in rat,and the reactivity of superior mesenteric artery (SMA) to norepinephrine (NE) was observed. A3AR expression at protein level and mRNA level were measured by Western blotting and RT-PCR respectively. RESULTS:The vascular reactivity of SMA to NE after hemorrhagic shock (40 mmHg) was decreased significantly in a biphasic response manner. The expression of A3AR mRNA in SMA after hemorrhagic shock decreased without significant difference. The expression of A3AR protein has a slight increase without statistical difference after 30 min of hemorrhagic shock and then has a significant decrease (especially at 2 h and 4 h after hemorrhagic shock). The usage of IB-MECA,a selective A3AR agonist,significantly increased the responsiveness of SMA to NE in hemorrhagic shock in rat. MRS1523,the selective A3AR antagonist,significantly abolished the restoration of the vascular reactivity to NE by IB-MECA in hemorrhagic shock in rat. CONCLUSION:A3AR plays a role in the modulation of vascular responsiveness to NE in hemorrhagic shock in rat,and the selective agonist of A3AR could restore the reactivity of SMA to NE in hemorrhagic shock in rat.