Adenosine is a neuromodulator that interacs with four adenosine receptors, A(1), A(2A), A(2B) and A(3). Adenosine receptors are new inroads in treating neuropathic pain. Even better, these compounds are inroads to treating gliopathic pain. Gliopathic pain is a new name for the chronic wind-up state of glia and neurons in chronic painstates we see in diabetic neuropathy, herpes zoster and many related painstates.

Selective A(1) agonists and antagonists, reached clinical trials for the treatment of different diseases:

A(1) agonists are clinical candidates for atrial arrhythmias, angina, type 2 diabetes and in chronic pain. ^[1]  

N6-cyclopentyladenosine (CPA) is a selective adenosine A1 receptor (A1R) agonist and this compound in rats with neuropathic pain induced by spinal nerve ligation could reduced thermal hyperalgesia and mechanical allodynia, which could last 6h and 10h, respectively (n=6/group, P<0.05). Spinal application of CPA depressed long-term potentiation (LTP) of A- and C-fiber evoked field potentials, mechanisms thought to play an improtant role in neuropathic pain.^[2] 

Adenosine 2A receptor (A2AR) stimulation decrease pro-inflammatory cytokine release and increase release of interleukin-10 (IL-10), an anti-inflammatory cytokine. Growing literature supports that glial proinflammatory cytokines importantly contribute to neuropathic pain, that is why the new term gliopathic pain has been coined. 

A single intrathecal injection of the A(2A)R agonists 4-(3-(6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl)prop-2-ynyl)piperidine-1-carboxylic acid methyl ester (ATL313) or 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine HCl (CGS21680), 10-14 d after CCI versus sham surgery, produced a long-duration reversal of mechanical allodynia and thermal hyperalgesia for at least 4 weeks.

An A(2A)R antagonist [ZM241385 (4-(2-[7-amino-2-(2-furyl)(1,2,4)triazolo(2,3-a)(1,3,5)triazin-5-ylamino]ethyl)phenol)] coadministered intrathecally with ATL313 abolished the action of ATL313 in rats with neuropathy-induced allodynia but had no effect on allodynia in the absence of the A(2A)R agonist.

ATL313 attenuated CCI-induced upregulation of spinal cord activation markers for microglia and astrocytes in the L4-L6 spinal cord segments both 1 and 4 weeks after a single intrathecal ATL313 administration.

Neutralizing IL-10 antibodies could abolished the effect of ATL313 on neuropathic pain. In addition, IL-10 mRNA was significantly elevated in the CSF cells collected from the lumbar region.

Activation of A(2A)Rs thus may be a novel, therapeutic approach for the treatment of neuropathic pain by increasing IL-10 in the immunocompetent cells of the CNS.^[3] 

These effects are not unique to one A2AR-selective compound, as comparable results were obtained using two structurally distinct A2AR-selective agonists (ATL313 and CGS21680). Previous studies reported that A2AR activation reduces neuroinflammatory symptoms in spinal cord injury, including motor deficits and markers of neuronal injury.

Adenosine modulation like in the studies above, may reduce neuropathic pain via activation of adenosine receptors either/or within spinal cord or resident or recruited immunocompetent cells within meninges or CSF. 

The A(1)AR antagonists currently in clinical development are KW3902, BG9928, and SLV320. All three have high nanomolar affinity for the human (h) A(1)AR subtype  In the A(1)AR agonist area, clinical candidates have been discovered for the following conditions: atrial arrhythmias (tecadenoson, selodenoson and PJ-875); Type II diabetes and insulin sensitizing agents (GR79236, ARA, RPR-749, and CVT-3619); and angina (BAY 68-4986).

The challenges associated with the development of any A(1)AR agonist are to obtain tissue-specific effects but avoid off-target tissue side effects and A(1)AR desensitization leading to tachyphylaxis. 

T-62 is an A(1)AR allosteric enhancer that is currently being evaluated in clinical trials as a potential treatment for neuropathic pain. ^[4] 

Under construction 

December 2010, prof. dr. Jan M. Keppel Hesselink 

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