Electroacupuncture modulates v1PAG release of GABA through presynaptic cannabinoid CB1 receptors

Department of Medicine, University of California, Irvine, CA 92697, USA.
Journal of Applied Physiology (Impact Factor: 3.43). 05/2009; 106(6):1800-9. DOI: 10.1152/japplphysiol.91648.2008
Source: PubMed

ABSTRACT Previous studies have demonstrated that electroacupuncture (EA) attenuates sympathoexcitatory reflex responses by activating a long-loop pathway involving the hypothalamic arcuate nucleus (ARC), midbrain ventrolateral periaqueductal gray (vlPAG), and rostral ventrolateral medulla (rVLM). Neurons in the ARC provide excitatory input to the vlPAG, whereas the vlPAG inhibits neuronal activity in the rVLM. gamma-Aminobutyric acid (GABA) and glutamate (Glu) have been identified in the vlPAG. Endocannabinoids (ECs), acting as atypical neurotransmitters, inhibit the release of both neurotransmitters in the hypothalamus and midbrain through a presynaptic cannabinoid type 1 (CB(1)) receptor mechanism. The EC system has been observed in the dorsal but not in the vlPAG. Since it is uncertain whether ECs influence GABA and Glu in the vlPAG, the present study tested the hypothesis that EA modulates the release of these neurotransmitters in the vlPAG through a presynaptic CB(1) receptor mechanism. We measured the release of GABA and Glu simultaneously by using HPLC to assess samples collected with microdialysis probes inserted unilaterally into the vlPAG of intact anesthetized rats. Twenty-eight min of EA (2 Hz, 2-4 mA, 0.5 ms) at the P5-6 acupoints reduced the release of GABA by 39% during EA and by 44% 15 min after EA. Thirty-five minutes after EA, GABA concentrations returned to pre-EA levels. In contrast, sham EA did not change the vlPAG GABA concentration. Blockade of CB(1) receptors with AM251, a selective CB(1) receptor antagonist, reversed the EA-modulated changes in GABA concentration, whereas microinjection of vehicle into the vlPAG did not alter EA-modulated GABA changes. In addition, we observed no changes in the vlPAG Glu concentrations during EA, although the baseline concentration of Glu was much higher than that of GABA (3,541 +/- 373 vs. 33.8 +/- 8.7 nM, Glu vs. GABA). These results suggest that EA modulates the sympathoexcitatory reflex responses by decreasing the release of GABA, but not Glu, in the vlPAG, most likely through a presynaptic CB(1) receptor mechanism.

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    • "And Fusumada et al. [126] proved that by inserting EA at " Zusanli " (ST36), EA could induce analgesic effect along with the increasing expression of GABA in PAG. Also, Fu and Longhurst [127] and Tjen-A-Looi et al. [128] studies reported that EA decreases the release of GABA in ventrolateral PAG, by modulating the sympathoexcitatory reflex responses through endocannabinoids. "
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    ABSTRACT: Neuropathic pain remains as one of the most difficult clinical pain syndromes to treat. Electroacupuncture (EA), involving endogenous opioids and neurotransmitters in the central nervous system (CNS), is reported to be clinically efficacious in various fields of pain. Although multiple experimental articles were conducted to assess the effect of EA-induced analgesia, no review has been published to assess the efficacy and clarify the mechanism of EA on neuropathic pain. To this aim, this study was firstly designed to evaluate the EA-induced analgesic effect on neuropathic pain and secondly to guide and help future efforts to advance the neuropathic pain treatment. For this purpose, articles referring to the analgesic effect of acupuncture on neuropathic pain and particularly the work performed in our own laboratory were analyzed. Based on the articles reviewed, the role of spinal opioidergic, adrenergic, serotonergic, cholinergic, and GABAergic receptors in the mechanism of EA-induced analgesia was studied. The results of this research demonstrate that μ and δ opioid receptors, α 2-adrenoreceptors, 5-HT1A and 5-HT3 serotonergic receptors, M1 muscarinic receptors, and GABAA and GABAB GABAergic receptors are involved in the mechanisms of EA-induced analgesia on neuropathic pain.
    Evidence-based Complementary and Alternative Medicine 07/2013; 2013:436913. DOI:10.1155/2013/436913 · 1.88 Impact Factor
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    • "Earlier studies have demonstrated that the cannabinoid receptor system has therapeutic potential in curing inflammatory diseases, such as rheumatoid arthritis [7]. Electroacupuncture (EA) has been suggested by some researchers to be able to modulate neural responses by decreasing the release of gamma-aminobutyric acid in the brain, most likely through a presynaptic cannabinoid receptor 1 (CB1) mechanism [8]. Given the analgesic effects of EA and the importance of the endocannabinoid system in pain modulation, we hypothesized that the action of EA on inflammatory pain may be attributable to increases in the expression of the CB1 receptor. "
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    ABSTRACT: Electroacupuncture (EA) has been regarded as an alternative treatment for inflammatory pain for several decades. However, the molecular mechanisms underlying the antinociceptive effect of EA have not been thoroughly clarified. Previous studies have shown that cannabinoid CB1 receptors are related to pain relief. Accumulating evidence has shown that the CB1 and dopamine systems sometimes interact and may operate synergistically in rat striatum. To our knowledge, dopamine D1/D2 receptors are involved in EA analgesia. In this study, we found that repeated EA at Zusanli (ST36) and Kunlun (BL60) acupoints resulted in marked improvements in thermal hyperalgesia. Both western blot assays and FQ-PCR analysis results showed that the levels of CB1 expression in the repeated-EA group were much higher than those in any other group (P = 0.001). The CB1-selective antagonist AM251 inhibited the effects of repeated EA by attenuating the increases in CB1 expression. The two kinds of dopamine receptors imparted different actions on the EA-induced CB1 upregulation in AA rat model. These results suggested that the strong activation of the CB1 receptor after repeated EA resulted in the concomitant phenomenon of the upregulation of D1 and D2 levels of gene expression.
    Evidence-based Complementary and Alternative Medicine 05/2013; 2013:393460. DOI:10.1155/2013/393460 · 1.88 Impact Factor
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    • "These include the arcuate and paraventricular nuclei in the hypothalamus (Li, Tjen-A-Looi, Guo, & Longhurst, 2010; Li, Tjen-A-Looi, & Longhurst, 2006; Tjen-A-Looi, Guo, & Longhurst, 2013), ventrolateral periaqueductal gray (vlPAG) in the midbrain (Li et al., 2009; Li, Tjen-A-Looi, Guo, et al., 2010), nucleus tractus solitarii (Tjen-A-Looi et al., 2012), rVLM (Moazzami, Tjen-A-Looi, Guo, & Longhurst, 2010; Tjen-A-Looi, Li, & Longhurst, 2003; Tjen-A- Looi et al., 2004), cVLM (Tjen-A-Looi et al., 2013), medullary raphe, particularly the raphe pallidus (Li, Tjen-A-Looi, & Longhurst, 2010b; Moazzami et al., 2010), and nucleus ambiguus (Guo, Li, & Longhurst, 2012; Tjen-A-Looi et al., 2012) in the medulla as well as the dorsal horn and intermediolateral columns of the spinal cord (Zhou, Mahajan, & Longhurst, 2009). Evoked somatic input is largely excitatory in these regions and relies most commonly on glutamate (Zhou, Fu, Guo, & Longhurst, 2007; Zhou, Fu, Tjen-A-Looi, Guo, & Longhurst, 2006), other excitatory neurotransmitters like acetylcholine (Li, Tjen-A-Looi, Guo, et al., 2010), or presynaptic disinhibition of inhibitory neurotransmitters (endocannabinoids acting to reduce release of g-aminobutyric acid or GABA) (Fu & Longhurst, 2009; Tjen-A-Looi et al., 2009). Acupuncture activates neurons in these regions, through a network of projections extending from the hypothalamus to more caudal regions like the vlPAG and rVLM and through inhibitory neurotransmitter mechanisms, including opioids (Li et al., 2009; Li, Tjen-A-Looi, & Longhurst, 2001; Tjen-A-Looi et al., 2003; Tjen-A-Looi, Li, & Longhurst, 2007), GABA (Fu & Longhurst, 2009; Tjen-A-Looi et al., 2007, 2009), nociceptin (Crisostomo et al., 2005; Tjen-A-Looi et al., 2007), or serotonin (Guo, Moazzami, Tjen-A- Looi, & Longhurst, 2008; Moazzami et al., 2010 "
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    ABSTRACT: Although mechanisms underlying acupuncture regulation of pain have been studied by a number of laboratories in many countries, much less is known about its ability to modulate cardiovascular function. In the last two decades, our laboratory has systematically investigated the peripheral and central neural mechanisms underlying acupuncture regulation of blood pressure. These observations account for acupuncture's distant actions and, to some extent, its local actions, with respect to the site of needling. Four fundamental findings have advanced our knowledge. First, point-specific effects of acupuncture underlie its cardiovascular actions. Second, variable regions in the supraspinal and spinal central nervous system that receive input from somatic afferent stimulation account for acupuncture's ability to modulate blood pressure. Thus, depending on the underlying situation, for example, high or low blood pressure, acupuncture modifies autonomic outflow by reducing activity in brain stem nuclei that participate in the primary response. Third, repetitive acupuncture through a molecular mechanism can cause prolonged cardiovascular effects that far outlast acupuncture stimulation. Fourth, there is a range of cardiovascular responsiveness to acupuncture that depends, at least in part, on interactions between neural modulators that synaptically regulate autonomic function in the brain stem. Thus, acupuncture has the capability of profoundly regulating cardiovascular function in patients with disease, for example, hypertension, and the experimental laboratory is directing best approaches to study its actions in humans.
    International Review of Neurobiology 01/2013; 111:257-71. DOI:10.1016/B978-0-12-411545-3.00013-4 · 2.46 Impact Factor
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