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Probing the Effects and Mechanisms of Electroacupuncture at Ipsilateral or Contralateral ST36-ST37 Acupoints on CFA-induced Inflammatory Pain.

ABSTRACT: Transient receptor potential vanilloid 1 (TRPV1) and associated signaling pathways have been reported to be increased in inflammatory pain signaling. There are accumulating evidences surrounding the therapeutic effect of electroacupuncture (EA). EA can reliably attenuate the increase of TRPV1 in mouse inflammatory pain models with unclear signaling mechanisms. Moreover, the difference in the clinical therapeutic effects between using the contralateral and ipsilateral acupoints has been rarely studied. We found that inflammatory pain, which was induced by injecting the complete Freund's adjuvant (CFA), (2.14 ± 0.1, p < 0.05, n = 8) can be alleviated after EA treatment at either ipsilateral (3.91 ± 0.21, p < 0.05, n = 8) or contralateral acupoints (3.79 ± 0.25, p < 0.05, n = 8). EA may also reduce nociceptive Nav sodium currents in dorsal root ganglion (DRG) neurons. The expression of TRPV1 and associated signaling pathways notably increased after the CFA injection; this expression can be further attenuated significantly in EA treatment. TRPV1 and associated signaling pathways can be prevented in TRPV1 knockout mice, suggesting that TRPV1 knockout mice are resistant to inflammatory pain. Through this study, we have increased the understanding of the mechanism that both ipsilateral and contralateral EA might alter TRPV1 and associated signaling pathways to reduce inflammatory pain.

SUBMITTER: Lu KW

PROVIDER: S-EPMC4764889 | biostudies-other | 2016 Feb

REPOSITORIES: biostudies-other

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Project description:Electroacupuncture (EA) treatment has proved to significantly decrease nociception in inflammatory nociception model by suppressing the phosphorylation of p38 mitogen-activated protein kinase (p38MAPK). However, repeated EA treatment results in gradual attenuation of its analgesic effects, which was defined as "EA tolerance." Recent studies have shown that let-7b-5p microRNA (miRNA) contributes to the EA tolerance. The present study aimed to explore the function of let-7b-5p in p38MAPK pathway and the development of EA tolerance in the inflammatory nociception. Dual luciferase reporter gene experiments were used in cortical neurons to determine the target gene locus of let-7b-5p. The threshold of nociception was assessed by tail flick latency (TFL) and paw withdrawal threshold (PWT). Western blots were used to measure the expression of mitogen-activated protein kinase phosphatase 1 (MKP-1) and phosphorylation level of p38MAPK after intracerebroventricular (ICV) injections of let-7b-5p agomir, antagomir, and controls. In vitro dual luciferase experiments demonstrated that the MKP-1-3' untranslated region (UTR) is a target of let-7b-5p. In vivo experiment, rat with repeated EA treatment exhibits gradual decrease in TFL and PWT, which showed formation of EA tolerance. This trend was delayed after IVC injection of let-7b-5p antagomir and facilitated after IVC injection of let-7b-5p agomir. The protein levels of MKP-1 in the EA+let-7b-5p antagomir group were significantly higher than in the EA + let-7b-5p agomir group. However, P-p38MAPK in the EA+let-7b-5p antagomir group was significantly lower than in the EA+let-7b-5p agomir group. By upregulating the p38MAPK pathway through the inactivation of the MKP-1 gene, let-7b-5p contributes to EA tolerance in complete Freund's adjuvant (CFA)-induced inflammatory nociception rats. Our work revealed the mechanism of EA tolerance and indicated that let-7b-5p could be targeted to improve the long-term effects of EA.

Project description:Background:Chronic shoulder pain (CSP) is a common disease causing pain and functional limitation, which is highly prevalent and has substantial negative effects on the quality of life. Acupuncture has gained popularity and has been accepted gradually by many countries because it can successfully treat patients with chronic pain, but the specific brain mechanisms under acupuncture treatment for CSP remain unclear. Therefore, in this study, we aimed to 1) compare the clinical effects between acupuncture at the contralateral and ipsilateral Tiaokou (ST 38) point in patients with unilateral shoulder pain and 2) explore how contralateral- and ipsilateral-acupuncture modulates the regional homogeneity (ReHo) of patients with CSP. Patients and methods:This was a pilot functional magnetic resonance imaging (fMRI) trial. Twenty-four patients with CSP were recruited and randomized to the contralateral acupuncture group (contra-group) and the ipsilateral acupuncture group (ipsi-group). All patients completed resting-state functional magnetic resonance imaging (fMRI) scans before and after acupuncture treatment. Shoulder pain intensity (visual analog scale [VAS]) and shoulder joint function (Constant-Murley score [CMS]) were used to evaluate clinical efficiency of treatment. ReHo was used to assess resting-state brain activity. Results:We found clinical improvement in decreasing pain intensity and increasing shoulder function in both groups, and the mean objective shoulder functional improvement in contra-group was better than that in ipsi-group (p = 0.010). Interestingly, the brain mechanism of contra-acupuncture at ST 38 was distinguishable from ipsi-acupuncture regarding ReHo values. Conclusion:Anterior cingulate cortex (ACC) may play a direct role in the regulation of brain by the contralateral acupuncture at ST 38 in patients with shoulder pain. On the contrary, the pathway of brainstem-thalamus-cortex may be likely to work in mechanism of acupuncture at ipsilateral ST 38. Significance:Our results indicate that the clinical effects and brain mechanisms are different between the stimulation given at contralateral and ipsilateral acupoints in patients with CSP and imply that the selection of either contralateral or ipsilateral acupuncture therapy to treat some chronic pain conditions is necessary.

Project description:Animal studies have led to the view that the acoustic medial olivocochlear (MOC) efferent reflex provides sharply tuned frequency-specific feedback that inhibits cochlear amplification. To determine if MOC activation is indeed narrow band, we measured the MOC effects in humans elicited by 60-dB sound pressure level (SPL) contralateral, ipsilateral, and bilateral noise bands as a function of noise bandwidth from 1/2 to 6.7 octaves. MOC effects were quantified by the change in stimulus frequency otoacoustic emissions from 40 dB SPL probe tones near 0.5, 1, and 4 kHz. In a second experiment, the noise bands were centered 2 octaves below probe frequencies near 1 and 4 kHz. In all cases, the MOC effects increased as elicitor bandwidth increased, with the effect saturating at about 4 octaves. Generally, the MOC effects increased as the probe frequency decreased, opposite expectations based on MOC innervation density in the cochlea. Bilateral-elicitor effects were always the largest. The ratio of ipsilateral/contralateral effects depended on elicitor bandwidth; the ratio was large for narrow-band probe-centered elicitors and approximately unity for wide-band elicitors. In another experiment, the MOC effects from increasing elicitor bandwidths were calculated from measurements of the MOC effects from adjacent half-octave noise bands. The predicted bandwidth function agreed well with the measured bandwidth function for contralateral elicitors, but overestimated it for ipsilateral and bilateral elicitors. Overall, the results indicate that (1) the MOC reflexes integrate excitation from almost the entire cochlear length, (2) as elicitor bandwidth is increased, the excitation from newly stimulated cochlear regions more than overcomes the reduced excitation at frequencies in the center of the elicitor band, and (3) contralateral, ipsilateral, and bilateral elicitors show MOC reflex spatial summation over most of the cochlea, but ipsilateral spatial summation is less additive than contralateral.

Project description:BackgroundIn unilateral neuropathic pain. e.g. after peripheral nerve injury, both positive and negative sensory signs occur often, accompanied by minor but equally directed contralateral sensory changes. To mimic this feature, we experimentally aimed to induce concomitant c-fibre sensitization and block in healthy subjects and analyzed the bilateral sensory changes by quantitative sensory testing (QST) using the protocol of the German Research Network on Neuropathic Pain.MethodsTwenty eight healthy subjects were firstly randomized in 2 groups to receive either topical capsaicin (0.6%, 12 cm2, application duration: 15 min.) or a lidocaine/prilocaine patch (25/25 mg, 10 cm2, application duration: 60 min.) on the right volar forearm. Secondly, 7-14 days later in the same area either at first capsaicin (for 15 min.) and immediately afterwards local anesthetics (for 60 min.) was applied (Cap/LA), or in inversed order with the same application duration (LA/Cap). Before, after each application and 7-14 days later a QST was performed bilaterally.StatisticsWilcoxon-test, ANOVA, p < 0.05.ResultsSingle application of 0,6% capsaicin induced thermal hypoesthesia, cold hypoalgesia, heat hyperalgesia and tactile allodynia. Lidocaine/prilocaine alone induced thermal and tactile hypoesthesia as well as mechanical and cold hypoalgesia, and a heat hyperalgesia (to a smaller extent). Ipsilaterally both co-applications induced a combination of the above mentioned changes. Significant contralateral sensory changes occurred only after the co-application with concomitant sensitization and hypoesthesia and comprised increased cold (Cap/LA, LA/Cap) and mechanical detection as well as cold pain threshold (LA/Cap).ConclusionThe present experimental model using combined application of capsaicin and LA imitates partly the complex sensory changes observed in patients with unilateral neuropathic pain and might be used as an additional surrogate model. Only the concomitant use both agents in the same area induces both positive and negative sensory signs ipsilaterally as well as parallel contralateral sensory changes (to a lesser extent).Trial registrationClinicalTrials.gov Identifier NCT01540877 , registered on 23 February 2012.

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Probing the Effects and Mechanisms of Electroacupuncture at Ipsilateral or Contralateral ST36-ST37 Acupoints on CFA-induced Inflammatory Pain.

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