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AcupunctureThe Seen, Unseen, and Adenosine
Abstract & Commentary
By Russell H. Greenfield, MD, Editor
Synopsis: In this exquisite set of methodical laboratory investigations, researchers tested whether adenosine might play a pivotal role in the analgesic effects associated with acupuncture. Their results suggest that the search for a mechanism of action behind this traditional therapy may be near its end.
Source: Goldman N, et al. Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture. Nature Neurosci 2010;13:883-889; commentary: Zylka MJ. Needling adenosine receptors for pain relief. Nature Neurosci 2010;13:783-784.
The traditional explanation for acupuncture's therapeutic effects have focused on the movement of qi, or the life force energy within and surrounding each of us. The placement of needles in carefully detailed locations on the body for the management of different health conditions as handed down across millennia is now commonplace, but a mere 40 years ago it fell more into the realm of mystery, if not in some people's minds, voodoo. Modern research instruments and some of the great scientific minds of our time have attempted to unravel what, if anything, happens during acupuncture therapy but puzzle pieces have always been left missing. That is, perhaps, until now.
The authors of this terrific investigation extrapolated well-accepted data on the activity of the nucleotides ATP, ADP, and AMP to explore in a murine pain model whether adenosine might be important to the analgesic effects ascribed to acupuncture. They knew that the aforementioned nucleotides are acted upon by ectonucloetidases that degrade them producing adenosine, and first sought to determine whether extracellular concentrations of adenosine increase during acupuncture. Samples of interstitial fluid were collected from near the "Zusanli point," located a few mm away for the midline of the knee. Levels of adenine nucleotides and adenosine were quantified using high-performance liquid chromatography before, during, and after acupuncture in association with gentle manual rotation of the needle every 5 minutes over the course of a 30-minute session. Levels of all purine levels increased locally. Adenosine concentration increased ~24-fold (253.5 ± 81.1 nM from a baseline of 10.6 ± 6.7 nM). Extracellular ATP levels returned to baseline after acupuncture, but those of adenosine, AMP, and ADP remained significantly elevated (adenosine and AMP, P < 0.01; ADP, P < 0.05) at 60 min. Thus, the researchers showed that adenosine was released during acupuncture.
Next, they explored whether adenosine was central to the analgesic effects of acupuncture by testing the effect of a selective A1 receptor agonist (CCPA) in mouse models of chronic pain. Injection of an inflammatory compound into the right paw resulted in mechanical and thermal allodynia (pain due to a stimulus that normally does not induce pain) in the same paw. When CCPA was injected into the Zusanli point there developed a marked increase in the threshold to pain in response to touch and heat and a reduction in mechanical allodynia. Further studies included mice lacking the A1 adenosine receptor and concluded that CCPA only reduced hypersensitivity in the presence of the A1 receptor.
The study authors next created a model of neuropathic pain by ligating the sciatic nerve, with peak pain levels being reached in 5-7 days. When CCPA was injected into the Zusanli point of the ipsilateral leg, a reduction in discomfort compatible with that seen in the chronic pain model was elicited. However, when CCPA was injected into the contralateral leg there was no pain relief. Thus, the authors concluded the action of CCPA is mediated through local A1 receptors. The researchers injected saline instead of CCPA into the Zusanli point and found no change in pain threshold.
The researchers then recorded in vivo responses of the left anterior cingulate cortex (ACC) to painful stimulation of the right foot and found that high-intensity stimulation produced consistent field excitatory postsynaptic potentials (fEPSPs) in the ACC with a latency of ~40 ms, reflecting the involvement of a polysynaptic pathway. Injection of CCPA into the contralateral leg's Zusanli point had no effect on fEPSPs, showing that CCPA did not act centrally; however, when CCPA was injected into the ipsilateral leg, a significant decrease in fEPSP amplitude was seen, occurring as soon as 6 minutes after injection. Thus, CCPA exerts its actions locally.
The researchers then employed a similar strategy to assess the effects of acupuncture on fEPSP amplitude recorded in the left ACC from painful stimulation of the right leg. Acupuncture of the left Zusanli point created no effect; however, when the ipsilateral Zusanli point was needled, fEPSP amplitude decreased. fEPSP amplitude was maximally reduced to 53.7 ± 7.2% (P < 0.01) of baseline at 60 min. Of note, acupuncture did not alter fEPSP in mice lacking A1 receptors. An additional study used deoxycoformycin, an established inhibitor of enzymes involved in adenosine degradation, with resultant augmentation of the acupuncture-elicited rise in adenosine levels, as well as its anti-nociceptive effect.
The authors state that combined, these observations provide direct evidence for a role of adenosine in acupuncture-mediated analgesia and suggest that adenosine accumulates slowly in the extracellular space during acupuncture. They also suggest that specific pharmaceuticals that antagonize adenosine metabolism may enhance the duration of pain relief with acupuncture.
In some ways it seems the search for a plausible mechanism behind acupuncture's effects was a "holy grail" of sorts. Some practitioners simply trusted in the outcome of the intervention, while others held to the traditional belief that the qi could be manipulated in therapeutically effective ways; some found comfort in data suggesting central opiate activity plays an important role, while others thought any response to acupuncture therapy to be placebo in nature; still others wanted a definitive answer. Across the rage of philosophies espoused by practitioners comes a potential answer that seems hard to refute.
The researchers found not just adenosine was released following acupuncture, but so were ATP, ADP, and AMP. This suggests that adenosine is produced locally by the effects of ectonucleotidases. As the author of a commentary that accompanies the study points out, it will be interesting to see if the anti-nociceptive effects of acupuncture are blocked by ectonucleotidase inhibition.
a.enosine can increase or decrease pain depending upon which receptor is stimulated. Of the four adenosine receptors (A1R, A2AR, A2BR, and A3R), only A1R has anti-nociceptive effects when activated peripherally. And A1R is blocked by caffeine; thus, it appears that people undergoing acupuncture therapy should avoid caffeinated products at least around the time of their treatment.
In sound fashion, the researchers took us through a methodical exploration into the role of adenosine and A1 receptors in acupuncture-associated analgesia. Other pathways may be involved, too, but for the first time there is an explanation to the oft-heard question, "How does acupuncture work?" that should assuage hard-core scientists, while not disrespecting traditionalists. In addition, there is the promise of an integrative approach to pain relief using a combination of acupuncture and drug therapy to extend the duration of acupuncture's effects. In this paper, science and traditional belief have come together in a meaningful way that should help our patients find even greater relief from pain.