PAPupuncture.

PAPupuncture.  Stronger and lasts 100 times longer. 

I’m going to get all the boring background stuff about acupuncture out of the way first and then dive into this really interesting physiological factoid about an ectonucleotidase combined with acupuncture that has been discovered.  I’m going to save us all a whole lot of time by simply listing some background info on acupuncture to bring you up to speed on the basics and then we can move onto PAPupuncture.  

• Earliest evidence of acupuncture comes from the Tyrolean Alps along the border of Italy.  A 5300 year old mummified european was discovered with non-decorative tattoos along several traditional acupuncture points.  Forensics indicate these points align with the ailments and pain this bronze age male was experiencing.  Tentatively referred to as tattoo-acupuncture it represents a shift in world view about the possible origins of acupuncture. (1)

• The Mayans use thorns and cactus needles to prick points around the body for various conditions.  Dozens of these points line up with the traditional Chinese system.  This could indicate a pan-cultural discovery of acupuncture by different civilizations at different points in      history. 

• The earliest written hieroglyphics of acupuncture are found in China and date to ~1600 BCE.

• First evidence published on the acupuncture mechanism by Bruce Pomeranz in 1976 is titled Naloxone Blockade of Acupuncture Analgesia: Endorphin Implicated.  This is still the gold standard for acupuncture.  Multiple follow ups (dozens) have been performed supporting the importance of opioid endorphins as a lynchpin in acupuncture analgesia.

• Helene Langevin, a neuroscientist at the University of Vermont in 2001 published a ground breaking new mechanism for acupuncture, in essence comparing it to sustained stretching.  By twisting the acupuncture needle, it pulls on connective tissues (collagen and elastin) causing local extracellular matrix deformation.  This leads to the stimulation of a wide variety of mechano- and nociceptors.  Langevin hypothesized the acupuncture signal, via mechanotransduction, reaches local fibroblasts and begins a signal cascade resulting in a therapeutic cellular response including synthesis and release of growth factors, cytokines, enzymes, matrix components, and vasoactive substances.  In essence, twisting the acupuncture needle wraps up the unusually high concentration of connective tissue found at acupuncture points like a fork wrapping up spaghetti!  For acupuncturists, this is a noticeable effect and can be strong enough to prevent turning the needle after a few rotations!  This needle rotation produces an extremely strong signal without creating a noxious painful event while causing  downstream local cellular alterations beneficial to injury.   (2)

                                         

• The second important aspect of the stretch theory is the adaptation and modulation of the local mechanoreceptors thereby altering the perception of pain during normal body movement. (2)

• 2009 University of Michigan fMRI study demonstrates that acupuncture modulates the brain in two ways.  Acupuncture alters the specific pain signal by increasing opioid binding in brain centers that dampen pain including the cingulate, insula, caudate, thalamus and amygdala.  These are the same centers affected by morphine and other opioid pain relievers.  This study also demonstrated that these specific pain signal centers modulated by acupuncture are not affected by placebo although both do affect regions associated with the subjective interpretation of pain.  In other words, the “acupuncture effect” shares some of the same specific traits as your typical opiate along with some of the subjective traits of the placebo effect but in the end it is unique and different from both. (3)  

In summary, acupuncture has multiple routes for altering and improving injury and pain including changes in opioid endorphins in the CNS, local changes to extracellular matrix and adhesion molecules through mechanotransduction, inactivation of brain centers responsible for dampening pain similar to morphine and the subjective experience of pain associated with the placebo response.  



PAPUPUNCTURE:

           

In 2010, Maiken Nedergaard M.D. at the University of Rochester Medical Center published the basis of a surprising new take on the mechanism of acupuncture.  His lab discovered that the neurotransmitter adenosine was increased significantly after acupuncture.  The actual level of adenosine was 24 times greater after a 30 minute treatment.  Adenosine levels are important because of the anti-inflammatory properties and pain relieving effects they produce.  One of the four possible adenosine receptors (A1R2) is specific for blocking nociceptive (pain) effects peripherally.  Adenosine also has a very short half life of a few seconds so it acts as the bodies transient local anesthetic, imagine a temporary endogenous lidocaine.   (4)

Now the question to ask is how can we take advantage of this natural pain killer that goes away so quickly?  What if we could cause it to be continuously synthesized?  That is where the ectonucleotidase PAP comes in.  PAP stands for prostatic acid phosphatase and is important for one big reason, it creates adenosine from ATP.  This is significant because following injury ATP is spontaneously released to excite nociceptive neurons and PAP is able to convert the ATP into adenosine which can inhibit those same receptors bringing pain relief.

Previously PAP had been studied as a spinal injection to relieve pain by Mark Zylka PhD, at the University of North Carolina Medical School.  It demonstrated an effect equal to morphine but lasting for several days versus several hours. In 2012, he combined the knowledge that PAP creates adenosine with the observation that peripheral analgesia by acupuncture works because of adenosine level increase and attempted a new experiment.  Instead of a spinal injection he injected PAP into a typical acupuncture point and observed an improvement in pain that lasted 6 days, in some case a 100 times longer than acupuncture.  There appears to be no limit to the application of this enzyme for peripheral pain relief. UNC has already licensed PAP out to a pharmaceutical company for development and testing.  (5)

One important side note for acupuncturists reading this blog.  Caffeine is known to block the adenosine receptors which implies that patients should be counseled not to drink any coffee before or after an acupuncture treatment.  This would apply to future patients seeking out PAPupuncture when it becomes integrated into standard care. 

About the Author:
Patrick T. Paine L.Ac. is a retired acupuncturist spending his days lazily enjoying the good life while fitting in a little bit of time studying stem cells.  He would like to unravel the regulation of biological aging and make an album with his CIRM band.    

Citations:

1. Kean W.F., S. Tocchio, M. Kean, K.D. Rainsford.  2013. The musculoskeletal abnormalities of the Similaun Iceman ("ÖTZI"): clues to chronic pain and possible treatments. Inflammopharmacology 21:11-20
2.  Langevin, H.M., D.L. Churchill, and M.J. Cipolla.  2001.  Mechanical signaling through connective tissue: a mechanism for the therapeutic effect of acupuncture.  The FASEB journal 15: 2275-2282
3.  Harris, R.E., J Zubieta, D.J. Scott, V. Napadow, R.H. Gracely, and D.J. Clauw. 2009. Traditional Chinese acupuncture and placebo (sham) acupuncture are differentiated by their effects on u-opiod receptors.  Journal of Neuroimage 47: 1077-1085
4. Goldman, N., M. Chen, T. Fujita, Q. Xu, W. Peng, W. Liu, T.K. Jensen, T. Pei, et al.  2010. Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture.  Nature Neuroscience, DOI: 10.1038/nn.2562
5.  Zylka, M.J. and J. Hurt. 2012 Papupuncture has localized and long-lasting antinociceptive effects in mouse models of acute and chronic pain.  Molecular Pain 8:28