Adenosine both causes and relieves pain

The Two Faces of Adenosine | Pain Research Forum – by Matthew Soleiman on 26 Jul 2016

Over several decades, adenosine—a purine nucleoside involved in many physiological and pathophysiological processes—has gained a reputation as a molecule that relieves pain.

But there have also been scattered reports that adenosine can produce pain.

Now, new research led by Yang Xia, University of Texas Medical School at Houston, US, helps make sense of adenosine’s dual nature.

mice with a deficiency in adenosine deaminase (ADA), an enzyme needed for the breakdown of adenosine, had sustained levels of circulating adenosine, which promoted mechanical and thermal pain sensitivity 

the increased pain sensitivity stemmed from adenosine binding to its A2B receptor on myeloid cells, resulting in a surge in circulating levels of an inflammatory complex

This complex, composed of the cytokine interleukin-6 (IL-6) and its soluble receptor (sIL-6R), in turn activated dorsal root ganglion (DRG) neurons, increasing expression of the transient receptor potential vanilloid type 1 (TRPV1) ion channel and pain.

A dark side

In the 1970s,  researchers first took notice that adenosine could relieve pain through its A1 receptor, one of four adenosine receptors. As a result, “there’s been interest for over 20 years in developing A1 receptor agonists as novel analgesics,”

But how adenosine causes pain has been less clear (Sawynok, 2015).

For example, A2A receptors can spur or halt pain, depending on where they are located.

Despite this uncertainty, persistently high levels of adenosine are known to promote inflammation, sickling, and tissue damage, but past studies had examined the effects only of acute increases in adenosine.

Thus, Xia and colleagues wondered if sustained increases of adenosine lead to chronic pain. To test that idea, they examined homozygous knockout mice missing ADA, which exhibit increased levels of adenosine and die because of severe metabolic disturbances (as is the case in people lacking the enzyme)

Polyethylene glycol-ADA (PEG-ADA), a US Food and Drug Administration-approved enzyme therapy used to treat people with ADA deficiency, metabolizes adenosine to prevent its excess accumulation and is also used to keep experimental mice alive.

“chronically accumulated adenosine in the plasma contributed to pain,” said Xia.

The authors next tried to determine through which receptors adenosine acted to cause the observed pain sensitivity

they administered PBS or different antagonists selective for each of adenosine’s four receptors to ADA-deficient mice.

Only the A2B receptor antagonist reversed the mechanical and thermal sensitivity seen in ADA-deficient mice.

Similarly, ADA-deficient mice that genetically lacked the A2B receptor showed less sensitivity on both measures.

Chronic pain seemed then to require a receptor different from those involved in analgesia.

To determine whether adenosine acted directly on pain-signaling neurons, the researchers applied an adenosine analog called NECA to dorsal root ganglia (DRG) neurons from wild-type mice.

These findings suggested that adenosine did not act directly on DRG neurons, leaving an unidentified pathway from adenosine to TRPV1 activation and pain.

A neuroimmune interaction

they asked whether the cytokine tied adenosine to chronic pain.

the authors found no evidence that IL-6 directly stimulated DRG neurons,

Because levels of adenosine and IL-6 were comparable in all three models examined in the study, the authors say this strengthens the case that innate immune cells release IL-6 to drive chronic pain.

“We really think that myeloid cells become sensitive to adenosine, resulting in more cytokines.

These cytokines form complexes, transactivating neurons to change gene expression and cause hypersensitivity,” said Xia.

Overall, the findings could help researchers reconcile how adenosine can be both pro- and anti-nociceptive.

As Sawynok points out, these opposing effects could be explained by varying amounts of adenosine likely to be present under different conditions, and adenosine’s varying affinity for different receptors.

under conditions like chronic inflammation, adenosine would reach levels high enough to recruit the A2B receptor, producing chronic pain.

Because PEG-ADA is an FDA-approved drug, Xia suggests that the therapy might be a safe option for driving down adenosine levels in people with chronic pain. The results also highlight the therapeutic potential for developing drugs targeting the A2B receptor.


Matthew Soleiman is a neuroscientist-turned-science writer currently residing in Nashville, Tennessee. Follow him on Twitter @MatthewSoleiman.  


Sustained Elevated Adenosine via ADORA2B Promotes Chronic Pain through Neuro-immune Interaction.
Hu X, Adebiyi MG, Luo J, Sun K, Le T-TT, Zhang Y, Wu H, Zhao S, Karmouty-Quintana H, Liu H, Huang A, Wen Y E, Zaika OL, Mamenko M, Pochynyuk OM, Kellems RE, Eltzschig HK, Blackburn MR, Walters ET, Huang D, et al
Cell Rep. 2016 Jun 28; 16(1):106-19. Epub 2016 Jun 16.

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