Adenosina y dolor/Adenosine and pain

Efectos analgésicos diferentes de la adenosina entre dolor postoperatorio y dolor neuropático


Different analgesic effects of adenosine between postoperative and neuropathic pain.
Yamaoka G, Horiuchi H, Morino T, Miura H, Ogata T.
Spine Center, Ehime University Hospital, Tohon, Ehime 791-0295, Japan.
J Orthop Sci. 2013 Jan;18(1):130-6. doi: 10.1007/s00776-012-0302-0. Epub 2012 Sep 21.
Abstract
BACKGROUND: Adenosine is an endogenous neuromodulator in both the peripheral and central nervous systems. Adenosine inhibits pain signals by hyperpolarizing neuronal membrane. METHODS: To clarify the effects of adenosine on pain signals, we tested intrathecal adenosine injection in two neuropathic pains (spinal cord compression and chronic constriction of sciatic nerve) and postoperative pain (plantar incision). RESULTS: In all three kinds of pain models, significant shortening of withdrawal latencies to thermal stimulation were detected from 24 h to 1 week after the surgery. Significant improvements of pain sensation were observed in all three models after intrathecal injection of Cl-adenosine 24 h after surgery. At 72 h after surgery, intrathecal Cl-adenosine injection inhibited hyperalgesia in the two neuropathic pain models but not in the postoperative pain model. Adenosine A1R messenger RNA (mRNA) expression significantly decreased in the plantar incision model. Adenosine A1R protein levels also decreased compared with the other two models and normal control. CONCLUSIONS: These results suggest that adenosine effectively inhibits pain signals in neuropathic pain but is less effective in postoperative pain because of the decrease in adenosine A1 receptors.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553403/pdf/776_2012_Article_302.pdf





Adenosina A oral activa agonista de los receptores con efectos antinociceptivos en ratones

Orally active adenosine A(1) receptor agonists with antinociceptive effects in mice.
Korboukh I, Hull-Ryde EA, Rittiner JE, Randhawa AS, Coleman J, Fitzpatrick BJ, Setola V, Janzen WP, Frye SV, Zylka MJ, Jin J.
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
J Med Chem. 2012 Jul 26;55(14):6467-77. doi: 10.1021/jm3004834. Epub 2012 Jul 16.
Abstract
Adenosine A(1) receptor (A(1)AR) agonists have antinociceptive effects in multiple preclinical models of acute and chronic pain. Although numerous A(1)AR agonists have been developed, clinical applications of these agents have been hampered by their cardiovascular side effects. Herein we report a series of novel A(1)AR agonists, some of which are structurally related to adenosine 5'-monophosphate (5'-AMP), a naturally occurring nucleotide that itself activates A(1)AR. These novel compounds potently activate A(1)AR in several orthogonal in vitro assays and are subtype selective for A(1)AR over A(2A)AR, A(2B)AR, and A(3)AR. Among them, UNC32A (3a) is orally active and has dose-dependent antinociceptive effects in wild-type mice. The antinociceptive effects of 3a were completely abolished in A(1)AR knockout mice, revealing a strict dependence on A(1)AR for activity. The apparent lack of cardiovascular side effects when administered orally and high affinity (K(i) of 36 nM for the human A(1)AR) make this compound potentially suitable as a therapeutic.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501123/pdf/nihms-415626.pdf




AMP es un agonista del receptor A1 de adenosina
AMP is an adenosine A1 receptor agonist.
Rittiner JE, Korboukh I, Hull-Ryde EA, Jin J, Janzen WP, Frye SV, Zylka MJ.
Department of Cell and Molecular Physiology, University of North Carolina Neuroscience Center, Chapel Hill, North Carolina 27599, USA.
J Biol Chem. 2012 Feb 17;287(8):5301-9. doi: 10.1074/jbc.M111.291666. Epub 2012 Jan 3.
Abstract
Numerous receptors for ATP, ADP, and adenosine exist; however, it is currently unknown whether a receptor for the related nucleotide adenosine 5'-monophosphate (AMP) exists. Using a novel cell-based assay to visualize adenosine receptor activation in real time, we found that AMP and a non-hydrolyzable AMP analog (deoxyadenosine 5'-monophosphonate, ACP) directly activated the adenosine A(1) receptor (A(1)R). In contrast, AMP only activated the adenosine A(2B) receptor (A(2B)R) after hydrolysis to adenosine by ecto-5'-nucleotidase (NT5E, CD73) or prostatic acid phosphatase (PAP, ACPP). Adenosine and AMP were equipotent human A(1)R agonists in our real-time assay and in a cAMP accumulation assay. ACP also depressed cAMP levels in mouse cortical neurons through activation of endogenous A(1)R. Non-selective purinergic receptor antagonists (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid and suramin) did not block adenosine- or AMP-evoked activation. Moreover, mutation of His-251 in the human A(1)R ligand binding pocket reduced AMP potency without affecting adenosine potency. In contrast, mutation of a different binding pocket residue (His-278) eliminated responses to AMP and to adenosine. Taken together, our study indicates that the physiologically relevant nucleotide AMP is a full agonist of A(1)R. In addition, our study suggests that some of the physiological effects of AMP may be direct, and not indirect through ectonucleotidases that hydrolyze this nucleotide to adenosine.

http://www.jbc.org/content/287/8/5301.full.pdf+html




Atentamente
Anestesiología y Medicina del Dolor
www.anestesia-dolor.org