More than 116 million Americans struggle with persistent pain. As current treatment options do not adequately address the wide spectrum of chronic pain presentations, acupuncture is a popular alternative. Yet, acupuncture remains controversial due to our incomplete understanding of its biological basis. In recent experiments we have shown that acupuncture is linked to an increase in the local concentration of adenosine at the acupoint, in both human subjects and in mice. Moreover, local administration of an adenosine A1 receptor agonist in the Zusanli acupoint in mice mimicked the analgesic actions of acupuncture. Other investigators have shown that local administration of PAP (an acid phosphatase that can convert AMP to adenosine) provides days of pain reduction. As most acupoints are located in close proximity to peripheral nerves, we speculate that local A1 receptor signaling in pain fibers can reduce the transmission of pro-algesic afferent input. Based on the findings that adenosine, delivered in the acupoint, potently reduces the conductance of A(delta) and C pain fibers in the sciatic nerve in mice with chronic pain, we propose to evaluate whether A1 receptor signaling in peripheral pain pathways constitutes a novel therapeutic strategy that could provide longer-lasting analgesia than acupuncture itself.
Aim 1 will evaluate A1 receptor mediated signaling in mouse models of persistent inflammatory pain. The compound action potential will be recorded in the sciatic nerve before and after manipulation of adenosine signaling at the Zusanli acupoint. A1 receptor KO mice will serve as a negative control. Importantly, these experiments will also evaluate whether caffeine (an adenosine receptor antagonist) nullifies acupuncture induced analgesia. This issue is important because no clinical trials to date have considered that caffeine may directly counteract the clinical benefits of acupuncture.
Aim 2 asks whether prolonged increases in adenosine A1 receptor signaling along axonal tracts can trigger a persistent suppression of pain in experimental models of chronic inflammatory pain. Preliminary data show that administration of CD73 (an ectonucleotidase that converts endogenous AMP to adenosine) in the Zusanli acupoint provides prolonged pain relief.
Aim 3, we will build on preliminary data showing that administration of CD73 in the Zusanli acupoint reduced the level of substance P in spinal cord in mice with inflammatory pain. Given adenosine's endogenous anti-inflammatory profile, we will test the hypothesis that the adenosine signaling along afferent tracts suppresses hyperalgesia, leading to a reduction of inflammatory mediators in the spinal cord;then compare the observed anti-inflammatory action with long-term acupuncture. The proposed experiments will advance our understanding of the molecular pathways involved in acute and long-lasting analgesic actions of adenosine signaling along peripheral pain pathways. We hope these studies lead to the development of novel therapeutic strategies for the treatment of chronic pain, with the additional aim of providing insight into the biological basis of acupuncture.

Public Health Relevance

Chronic pain is a major problem for more than 116 million Americans and a major burden for our society. We have recently unveiled the biological mechanism of acute analgesic action by traditional acupuncture. This proposal will study the molecular pathways of long-term analgesic action of adenosine signaling in acupuncture and present a novel therapeutic strategy to treat chronic pain.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project (R01)
Project #
1R01AT007945-01
Application #
8562613
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Huntley, Kristen V
Project Start
2013-09-30
Project End
2018-06-30
Budget Start
2013-09-30
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$288,092
Indirect Cost
$98,092
Name
University of Rochester
Department
Neurology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Achariyar, Thiyagaragan M; Li, Baoman; Peng, Weiguo et al. (2017) Erratum to: Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation. Mol Neurodegener 12:3
Fujita, Takumi; Feng, Changyong; Takano, Takahiro (2017) Presence of caffeine reversibly interferes with efficacy of acupuncture-induced analgesia. Sci Rep 7:3397
McConnell, Evan D; Wei, Helen S; Reitz, Katherine M et al. (2016) Cerebral microcirculatory failure after subarachnoid hemorrhage is reversed by hyaluronidase. J Cereb Blood Flow Metab 36:1537-52
Lou, Nanhong; Takano, Takahiro; Pei, Yong et al. (2016) Purinergic receptor P2RY12-dependent microglial closure of the injured blood-brain barrier. Proc Natl Acad Sci U S A 113:1074-9
Achariyar, Thiyagaragan M; Li, Baoman; Peng, Weiguo et al. (2016) Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation. Mol Neurodegener 11:74
Sreetama, S C; Takano, T; Nedergaard, M et al. (2016) Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis. Cell Death Differ 23:596-607
Fujita, Takumi; Chen, Michael J; Li, Baoman et al. (2014) Neuronal transgene expression in dominant-negative SNARE mice. J Neurosci 34:16594-604