Electroacupuncture activates corticotrophin-releasing hormone-containing neurons in the paraventricular nucleus of the hypothalammus to alleviate edema in a rat model of inflammation

Center for Integrative Medicine, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
BMC Complementary and Alternative Medicine (Impact Factor: 2.02). 02/2008; 8(1):20. DOI: 10.1186/1472-6882-8-20
Source: PubMed


Studies show that electroacupuncture (EA) has beneficial effects in patients with inflammatory diseases. This study investigated the mechanisms of EA anti-inflammation, using a rat model of complete Freund's adjuvant (CFA)-induced hind paw inflammation and hyperalgesia.
Four experiments were conducted on male Sprague-Dawley rats (n = 6-7/per group). Inflammation was induced by injecting CFA into the plantar surface of one hind paw. Experiment 1 examined whether EA increases plasma adrenocorticotropic hormone (ACTH) levels. Experiments 2 and 3 studied the effects of the ACTH and corticotropin-releasing hormone (CRH) receptor antagonists, ACTH(11-24) and astressin, on the EA anti-edema. Experiment 4 determined whether EA activates CRH neurons in the paraventricular nucleus of the hypothalammus. EA treatment, 10 Hz at 3 mA and 0.1 ms pulse width, was given twice for 20 min each, once immediately post and again 2 hr post-CFA. Plasma ACTH levels, paw thickness, and paw withdrawal latency to a noxious thermal stimulus were measured 2 h and 5 h after the CFA.
EA significantly increased ACTH levels 5 h (2 folds) after CFA compared to sham EA control, but EA alone in naive rats and CFA alone did not induce significant increases in ACTH. ACTH(11-24) and astressin blocked EA anti-edema but not EA anti-hyperalgesia. EA induced phosphorylation of NR1, an essential subunit of the N-methyl-D-aspartic acid (NMDA) receptor, in CRH-containing neurons of the paraventricular nucleus.
The data demonstrate that EA activates CRH neurons to significantly increase plasma ACTH levels and suppress edema through CRH and ACTH receptors in a rat model of inflammation.

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    • "In the present study, we observed that EA has suppressed paw edema induced by intraplantar CFA. This is supported by previous studies reporting that EA significantly inhibits edema compared to sham EA control in CFA-injected rat [12, 14, 30]. A previous study reported that a single or repetitive EA could reduce mechanical hyperalgesia, but not thermal hyperalgesia, in CFA-inflammatory pain rats [31]. "
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    ABSTRACT: Activation of mitogen-activated protein kinases (MAPKs), especially p38 MAPK, plays an important role in the development of central sensitization related to persistent inflammatory pain. Electroacupuncture (EA) is well known to relieve persistent inflammatory pain. However, little is known about relationship between EA and p38 MAPK. Inflammatory pain rat model was induced by intraplantar injection of complete Freund's adjuvant (CFA). Male adult SD rats were randomly divided into the saline group, CFA group, and CFA + EA group. EA (constant saquare wave, 2 Hz and 100 Hz alternating frequencies, intensities ranging from 1 to 2 mA) was applied to bilateral "Zusanli" (ST 36) and "Kunlun" acupoints (BL 60) for 30 min, once per day. The paw edema and paw withdrawal threshold (PWT) were measured at preinjection and days postinjection 1, 3, and 14. Spinal p-p38MAPK- immunoreactivty (p-p38MAPK-IR) cells were detected by immunohistochemistry at postinjection day 3 and 14. EA significantly inhibited paw edema at postinjection days 14 and increased PWT at postinjection days 3 and 14. Moreover, the increasing number of spinal p-p38MAPK-IR cells which was induced by CFA injection was suppressed by EA stimulation. These results indicate that anti-inflammatory and analgesic effect of EA might be associated with its inhibition of spinal p38 MAPK activation and thereby provide a potential mechanism for the treatment of inflammatory pain by EA.
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    • "It has been reported that EA has different effects on healthy and pathological conditions. For example, EA significantly increases plasma adrenocorticotropic hormone (ACTH) and corticosterone levels in inflamed but not in naive rats (Li et al., 2008). "
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    ABSTRACT: It has been reported that intracerebroventricular injection of a μ receptor antagonist blocked 2 but not 100Hz electroacupuncture (EA)-produced analgesia in an uninjured animal model. Because persistent pain changes neural response to external stimulation, we hypothesized that the mechanisms of EA anti-hyperalgesia may be different in persistent pain than in health. Hyperalgesia, decreased paw withdrawal latency (PWL) to a noxious thermal stimulus, was induced by subcutaneously injecting complete Freund's adjuvant (CFA) into the hind paws of rats. Selective antagonists against μ (CTOP: D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH2, 6.25 nmol) and κ (Nor-BIN: nor-binaltorphimine, 10 nmol) opioid receptors were infused into the rostral ventromedial medulla (RVM) 10 min before a 30-min EA treatment at acupoint Huantiao (GB30) 1h 30 min post-CFA. PWL was measured before and 2.5 post-CFA. Both 10 Hz and 100 Hz EA-produced anti-hyperalgesia were blocked by intra-RVM μ, but not κ, receptor antagonists. Double immunofluorescence staining demonstrated that μ receptor-containing neurons were GABAnergic and that GABAa receptor-containing neurons were serotonergic in the RVM. The results demonstrated an involvement of RVM μ, but not κ, receptors in EA-produced anti-hyperalgesia. In summary, EA may induce release of endogenous endomorphins that activate μ opioid receptors in GABAnergic neurons to suppress the release of GABA. This removes the tonic inhibition of GABA on serotonergic neurons in the RVM, and activation of these serotonergic neurons inhibits pain. EA may be used as complementary treatment for inflammatory pain.
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    • "Although studies have not been able to fully explain the mechanism of acupuncture, it has been proposed that acupuncture works through its effect on neurotransmitters and neurohormones [20] [21] [22] [23]. Animal research suggests that acupuncture accomplishes its anesthesia effect by stimulating nerves in the muscle, which then relay the signal to the spinal cord, midbrain, and hypothalamus-pituitary system, which then lead to the release of neurotransmitters and hormones, that is, endorphins and enkephalins [24] [25] [26]. Other mechanisms such as activation of descending pain inhibiting pathways, deactivation of the limbic system, cortical cerebral vasodilation causing release of neuropeptide, and inhibition of the release of inflammatory factors have also been suggested to explain the effect of acupuncture analgesia [27] [28] [29] [30] [31]. "
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