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It is known that interleukin-17 (IL-17) is associated with autoimmune disorders and that peripheral IL-17 plays a role in arthritis and neuropathic pain. The present study investigated the possibility of spinal cell expression of IL-17 during inflammatory pain and possible IL-17 involvement in such pain. Hyperalgesia was induced by injecting complete Freund adjuvant (CFA, 0.08mL, 40μg Mycobacterium tuberculosis) into one hind paw of the rat. Paw withdrawal latency (PWL) was tested before (-48h) and 2 and 24h after CFA injection to assess hyperalgesia. IL-17 antibody (0.2-2μg/rat) was given intrathecally (i.t.) 24h before CFA to block the action of basal IL-17 and 2h before each of 2 PWL tests to block CFA-induced IL-17. I.t. recombinant IL-17 (10-400ng per rat) was administered to naive rats to determine its effects on PWL and phosphorylated NR1 (p-NR1). p-NR1 modulates N-methyl-d-aspartate receptor (NMDAR) activity to facilitate pain. Spinal cords were removed for IL-17 immunostaining, double immunostaining of IL-17/cell markers and IL-17 receptor A (IL-17RA)/NR1, for Western blot testing of IL-17, p-NR1, IL-17RA, and GFAP, for in situ IL-17RA hybridization, and for real time polymerase chain reaction of IL-17RA. The data reveal that IL-17 is up-regulated in activated and nonactivated astrocytes; that IL-17RA is localized in NR1-immunoreactive neurons and up-regulated; and that IL-17 antibody at 2μg/rat significantly increased PWL (P<.05) and decreased p-NR1 and IL-17RA compared to control in CFA- and IL-17-injected rats. The results suggest that spinal IL-17 is produced by astrocytes and enhances p-NR1 to facilitate pain., (Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

We previously showed that electroacupuncture (EA) activates medulla-spinal serotonin-containing neurons. The present study investigated the effects of intrathecal 5,7-dihydroxytryptamine creatinine sulfate, a selective neurotoxin for serotonergic terminals, the 5-hydroxytryptamine 1A receptor (5-HT1AR) antagonist NAN-190 hydrobromide and the 5-HT2C receptor (5-HT2CR) antagonist SB-242,084 on EA anti-hyperalgesia. EA was given twice at acupoint GB30 after complete Freund's adjuvant (CFA) injection into hind paw. CFA-induced hyperalgesia was measured by assessing hind paw withdrawal latency (PWL) to a noxious thermal stimulus 30 min post-EA. Serotonin depletion and the 5-HT1AR antagonist blocked EA anti-hyperalgesia; the 5-HT2CR antagonist did not. Immunohistochemical staining showed that spinal 5-HT1AR was expressed and that 5-HT2CR was absent in naive and CFA-injected animals 2.5 h post-CFA. These results show a correlation between EA anti-hyperalgesia and receptor expression. Collectively, the data show that EA activates supraspinal serotonin neurons to release 5-HT, which acts on spinal 5-HT1AR to inhibit hyperalgesia.

Acupuncture and electro-acupuncture (EA) are now widely used to treat disorders like pain. We and others have shown previously that current frequency, intensity and treatment duration all significantly influence the anti-nociceptive effects of EA. There is evidence that stimulating sites also affect the antinociception, with EA applied ipsilaterally to the pain site being more effective under some pain states but contralateral EA under others. It was recently reported that local adenosine A1 receptors were responsible for ipsilateral acupuncture, but what mechanisms specifically mediate the anti-nociceptive effects of contralateral acupuncture or EA remains unclear. In the present study, we applied 100 Hz EA on the ipsi- or contra-lateral side of rats with inflammatory pain induced by intra-plantar injection of formalin, and reported distinct anti-nociceptive effects and mechanisms between them. Both ipsi- and contra-lateral EA reduced the paw lifting time in the second phase of the formalin test and attenuated formalin-induced conditioned place aversion. Contralateral EA had an additional effect of reducing paw licking time, suggesting a supraspinal mechanism. Lesions of rostral anterior cingulate cortex (ACC) completely abolished the anti-nociceptive effects of contra- but not ipsi-lateral EA. These findings were not lateralized effects, since injection of formalin into the left or right hind paws produced similar results. Overall, these results demonstrated distinct anti-nociceptive effects and mechanisms between different stimulating sides and implied the necessity of finding the best stimulating protocols for different pain states.

Ethnopharmacological Relevance: HLXL is a traditional Chinese medicine that has long been used in folk medicine for the treatment of chronic inflammatory diseases. However, the precise immunological mechanisms by which HLXL mediates its anti-inflammatory activity are not fully defined., Aim of the Study: To determine the effects of HLXL on antigen-specific immune parameters in adjuvant-induced inflammation model in the Lewis rat., Materials and Methods: Rats were fed daily with either HLXL (2.3g/kg) or vehicle (water) beginning 3 days before subcutaneous injection of heat-killed Mycobacterium tuberculosis H37Ra (Mtb), and then continued for another 6 days. After 9 days of Mtb injection, the draining lymph node cells were tested for T cell proliferative and cytokine responses against mycobacterial heat-shock protein 65 (Bhsp65). Moreover, sera were tested for anti-Bhsp65 antibodies and nitric oxide (NO)., Results: HLXL-treated rats showed reduced T cell proliferative response to Bhsp65 compared to control rats. Furthermore, HLXL suppressed IL-17 response but enhanced IL-10 response without much effect on IFN-gamma. HLXL treatment also reduced the levels of anti-Bhsp65 antibodies but not that of NO., Conclusions: HLXL feeding modulated both the cellular and the humoral immune response to Bhsp65 favoring an anti-inflammatory milieu for the suppression of adjuvant-induced inflammation.

Background: 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., Design: 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., Results: 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., Conclusion: 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.

Although it has been shown that pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) facilitate perception of noxious inputs at the spinal level, the mechanisms have not been understood. This study determined the cell type that produces IL-1beta, the co-localization of IL-1 receptor type I (IL-1RI) and Fos and NR1 in the spinal cord, and the effects of IL-1 receptor antagonist (IL-1ra) on NR1 phosphorylation and hyperalgesia in a rat model of inflammatory pain. Phosphorylation of NR1, an essential subunit of the NMDA receptor (NMDAR), is known to modulate NMDAR activity and facilitate pain. Hyperalgesia was induced by injecting complete Freund's adjuvant (CFA, 0.08ml, 40microg Mycobacterium tuberculosis) into one hind paw of each rat. Paw withdrawal latency (PWL) was tested before CFA (-48h) for baseline and 2 and 24h after CFA to assess hyperalgesia. IL-1ra was given (i.t.) 24h before CFA to block the action of basal IL-1beta and 2h prior to each of two PWL tests to block CFA-induced IL-1beta. Spinal cords were removed for double immunostaining of IL-1beta/neuronal marker and IL-1beta/glial cell markers, IL-1RI/Fos and IL-1RI/NR1, and for Western blot to measure NR1 phosphorylation. The data showed that: (1) astrocytes produce IL-1beta, (2) IL-1RI is localized in Fos- and NR1-immunoreactive neurons within the spinal dorsal horn, and (3) IL-1ra at 0.01mg/rat significantly increased PWL (P<0.05) and inhibited NR1 phosphorylation compared to saline control. The results suggest that spinal IL-1beta is produced by astrocytes and enhances NR1 phosphorylation to facilitate inflammatory pain.

Background: Electroacupuncture (EA) has been reported to produce anti-edema and anti-hyperalgesia effects on inflammatory disease. However, the mechanisms are not clear. The present study investigated the biochemical mechanisms of EA anti-inflammation in a rat model., Methods: Three experiments were conducted on male Sprague-Dawley rats (n = 7-8/per group). Inflammation was induced by injecting complete Freund's adjuvant (CFA) subcutaneously into the plantar surface of one hind paw. Experiment 1 measured plasma corticosterone (CORT) levels to see if EA regulates CORT secretion. Experiment 2 studied the effects of the adrenal gland on the therapeutic actions of EA using adrenalectomy (ADX) rats. Experiment 3 determined whether a prototypical glucocorticoid receptor antagonist, RU486, affects EA anti-edema. EA treatment, 10 Hz at 3 mA and 0.1 ms pulse width, was given twice, for 20 min each, once immediately after CFA administration and again 2 h post-CFA. Plasma CORT levels, paw thickness, indicative of the intensity of inflammation, and paw withdrawal latency (PWL) were measured 2 h and 5 h after the CFA injection., Results: EA significantly increased plasma corticosterone levels 2 h (5 folds) and 5 h (10 folds) after CFA administration compared to sham EA control, but EA alone in naive rats and CFA alone did not induce significant increases in corticosterone. Adrenalectomy blocked EA-produced anti-edema, but not EA anti-hyperalgesia. RU486 (15 mul, 15 mug/mul), a prototypical glucocorticoid receptor antagonist, also prevented EA anti-edema., Conclusion: The data demonstrate that EA activates the adrenals to increase plasma corticosterone levels and suppress edema and suggest that EA effects differ in healthy subjects and in those with pathologies.

The involvement of the peripheral opioid system in modulating inflammatory pain has been well documented. This study aimed to investigate the possibility of electroacupuncture (EA)-mediated peripheral opioid release. Rats were injected with complete Freund's adjuvant in one of the hind paws to induce localized inflammatory pain. The pain behavioral changes were measured by paw withdrawal latency (PWL) to a noxious thermal stimulus. At day 5 of inflammation, rats received a second injection of saline or opioid antagonists into the inflamed paw, followed by EA at 30 Hz, 2 mA, and 0.1 ms for 30 minutes. The EA was conducted at acupuncture point GB30. A control was used in which needles were inserted at GB30 but no electrical stimulation was applied. Rats receiving EA showed a significantly longer PWL as compared with the control from 30 minutes to three hours after EA treatment. Intraplantar but not intraperitoneal injection of naloxone methiodide, a peripherally acting opioid receptor antagonist, eliminated the analgesic effect at 30 minutes after EA treatment. Intraplantar injection of an antibody against beta-endorphin and a corticotropin-releasing factor antagonist also produced a reduction in PWL in rats receiving EA. These data strongly suggest that peripheral opioids are released by EA at the inflammatory site.

It has been demonstrated that electroacupuncture (EA) significantly suppresses behavioral hyperalgesia in a rat model of persistent inflammatory pain and that neurokinin-1 (NK-1)/substance P (SP) receptors play important roles in nociception and hyperalgesia at the spinal cord level. The present study investigated spinal NK-1 receptor involvement in EA-produced suppression of hyperalgesia in a rat model of persistent inflammatory pain. The results showed that hind paw inflammation induced a significant increase of NK-1 receptor expression in the spinal dorsal horn and that this effect was significantly suppressed by EA. This suggests that EA-induced suppression of hyperalgesia is involved, at least partly, in the suppression of the spinal NK-1 receptors induced by sustained peripheral nociceptive input.

Our previous study showed that electroacupuncture (EA) significantly attenuated hyperalgesia in an animal model of persistent inflammatory pain. The present study was designed to show if Gi/o protein is involved in EA-produced anti-hyperalgesia. Spinal Gi/o-protein function was destroyed by intrathecal pretreatment with pertussis toxin (PTX). Seven days after the placement of an intrathecal PE-10 tube, PTX was injected into the intrathecal space of the lumbar spinal cord of rats. Seven days after PTX, complete Freund's adjuvant (CFA) was injected into the plantar surface of one hind paw of the rat to induce hyperalgesia in the injected paw. EA treatment was given at acupoint GB30 immediately post-CFA and then hyperalgesia was assessed by measuring the degree of decreased paw withdrawal latency (PWL) to a noxious thermal stimulus. The results showed that PTX pretreatment prevented EA-produced anti-hyperalgesia in the CFA inflammatory pain model but did not affect either baseline pain threshold or CFA-induced hyperalgesia. The data suggest that EA-produced anti-hyperalgesia is mediated by PTX-sensitive Gi/o proteins and the relevant signaling pathways.

Spinal nociceptive neural circuits undergo considerable changes during the postnatal period. This study showed that neonatal rats exhibited earlier upregulation and faster recovery of spinal preprodynorphin (PPD) mRNA than did the adults during complete Freund's adjuvant (CFA)-induced peripheral inflammation. These data suggest that the central nervous systems of neonates and adults respond differently to peripheral noxious inputs, a fact that should be considered when selecting pain treatment strategies for neonate populations.

Our previous study showed that electroacupuncture (EA), an adjuvant to conventional medicine, significantly attenuated hyperalgesia and inflammation. The present study is an evaluation of the potential synergism of EA and a subeffective dosage of indomethacin (INDO) in a rat model. Inflammation and hyperalgesia, manifesting as edema and decreased paw withdrawal latency (PWL) to a noxious stimulus, were induced by injecting complete Freund's adjuvant (CFA) subcutaneously into the plantar surface of one hind paw of the rat. EA treatments were given at acupoint GB30 immediately and 2 h post-CFA. INDO at 2 mg/kg was given (intraperitoneally) 40 min before the second EA. PWL and edema were measured prior to CFA and 2.5 and 5 h post-CFA. Ten and 100 Hz EA significantly inhibited CFA-induced hind paw hyperalgesia. Both low- and high-frequency EA combined with INDO enhanced antihyperalgesia compared to each component alone, and 10 Hz but not 100 Hz EA significantly reduced CFA-induced hind paw edema. A combination of low-frequency EA and INDO did not show synergistic inhibitory effects on edema. The results demonstrate that EA combined with INDO synergistically inhibits hyperalgesia and suggest an improved treatment strategy for inflammatory pain., (Copyright 2004 Elsevier Inc.)

The aging process is associated with various morphological and biochemical changes in the nervous system that may affect the processing of noxious inputs. This study showed greater hyperalgesia and up-regulation of spinal dynorphin (DYN) expression in aging than in young adult rats during CFA-induced peripheral inflammation. These data indicate that nociception is regulated differently in aging individuals, a fact that should be considered when selecting treatment strategies for aging populations with persistent pain.

Although studies demonstrate that electroacupuncture (EA) alleviates the sensory dimension of pain, they have not addressed EA's effect on the affective dimension. An inflammatory pain rat model, produced by a complete Freund adjuvant (CFA) injection into the hind paw, was combined with a conditioned place avoidance test to determine EA's effects and its underpinning mechanism on the affective dimension of pain. CFA-injected rats showed place aversion, i.e. the affective dimension of pain, by spending less time in a pain-paired compartment after conditioning than before, while saline-injected rats did not. CFA rats given EA treatment at GB30 before a post-conditioning test showed no aversion to the pain-paired compartment, indicating that EA inhibited the affective response. Intra-rostral anterior cingulate cortex (rACC) administration of a κ-, but not μ-opioid receptor antagonist, blocked EA action. These data demonstrate that EA activates opioid receptors in the rACC to inhibit the affective dimension of pain. [ABSTRACT FROM AUTHOR]

The involvement of the peripheral opioid system in modulating inflammatory pain has been well documented. This study aimed to investigate the possibility of electroacupuncture (EA)-mediated peripheral opioid release. Rats were injected with complete Freund’s adjuvant in one of the hind paws to induce localized inflammatory pain. The pain behavioral changes were measured by paw withdrawal latency (PWL) to a noxious thermal stimulus. At day 5 of inflammation, rats received a second injection of saline or opioid antagonists into the inflamed paw, followed by EA at 30 Hz, 2 mA, and 0.1 ms for 30 minutes. The EA was conducted at acupuncture point GB30. A control was used in which needles were inserted at GB30 but no electrical stimulation was applied. Rats receiving EA showed a significantly longer PWL as compared with the control from 30 minutes to three hours after EA treatment. Intraplantar but not intraperitoneal injection of naloxone methiodide, a peripherally acting opioid receptor antagonist, eliminated the analgesic effect at 30 minutes after EA treatment. Intraplantar injection of an antibody against β-endorphin and a corticotropin-releasing factor antagonist also produced a reduction in PWL in rats receiving EA. These data strongly suggest that peripheral opioids are released by EA at the inflammatory site. [Copyright &y& Elsevier]

Acupuncture has traditionally been used in China and is being increasingly applied in Western countries to treat a variety of conditions, including inflammatory disease. However, clinical trials investigating the effectiveness of the anti-inflammatory effects of acupuncture have yielded inconsistent results, andthe underlying mechanisms of acupuncture-produced anti-inflammation are unclear.To evaluate the effectiveness of electroacupuncture (EA) on inflammation in a rat model.Four experiments were conducted on male Sprague-Dawley rats (= 8–9 per group). Inflammation was induced by injecting complete Freund’s adjuvant (CFA) subcutaneously into the plantar surface of one hind paw of the rat. Experiment 1: To determine the effect of EA (10 and 100 Hz) versus sham treatment on inflammation. Experiment 2: To investigate the involvement of the adrenal glands on the effect of EA treatment using adrenalectomized (ADX) rats. Experiment 3: To determine the effects of EA on plasma levels of corticosterone. Experiment 4: To determine the effects of EA treatment versus immobilizationon such stress indicators as heart rate and blood pressure.At 10 Hz EA significantly reduced CFA-induced hind paw edema. The effect was partially blocked in the ADX rats. EA significantly increased plasma levels of corticosterone but produced no noticeable signs of stress.At 10 Hz but not 100 Hz, EA suppresses inflammation by activating the hypothalamus-pituitary-adrenal axis (HPA) and the nervous system. [ABSTRACT FROM AUTHOR]

We previously reported the anti-hyperalgesia of electroacupuncture (EA) on persistent inflammatory pain in an unrestrained, unsedated, and conscious rat model. Using this model, induced by injecting complete Freund''s adjuvant (CFA) into one hind paw, we systematically evaluated the anti-hyperalgesia of EA stimulation parameters (frequency, intensity, treatment duration, and pulse width). We assessed hyperalgesia by paw withdrawal latency (PWL) to a noxious thermal stimulus and found that 10- and 100-Hz EA frequencies at a current intensity of 3 mA produced the greatest anti-hyperalgesia, when compared to other parameters. Both frequencies significantly increased PWL in the early phases of hyperalgesia (2.5 and 24 h; p<0.05), and 10 Hz EA also significantly increased PWL in later phases (5 to 7 days; p<0.05). A sufficient but tolerable intensity of 3 mA was more effective than lower intensities (1–2 mA). A 20-min treatment produced better anti-hyperalgesia than longer and shorter (10 and 30 min) treatments. Acupoint specificity study demonstrated that GB30 produced significant EA anti-hyperalgesia, while Waiguan (TE5) and sham points, an abdominal point and a point at the opposite aspect of GB30, did not. The spinal Fos protein expression study demonstrated that the optimal EA selectively suppressed Fos expression in superficial laminae (I/II) and activated it in deeper laminae (III/IV) of the spinal dorsal horn. The results suggest that the EA anti-hyperalgesia is parameter-dependent and point-specific, and they provide important information for designing further clinical acupuncture research on persistent inflammatory pain. [Copyright &y& Elsevier]

Our previous study showed that electroacupuncture (EA) significantly attenuated inflammatory hyperalgesia. It has also been reported that EA analgesia in uninjured animals is mediated by μ and δ opioid receptors at 2–15 Hz and by κ opioid receptor at 100 Hz. Because persistent pain changes neural response to external stimulation, we hypothesized that (1) the mechanisms of EA anti-hyperalgesia may be different under conditions of persistent pain and that (2) combining EA with a sub-effective dose of morphine could enhance EA anti-hyperalgesia. 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 (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH2, CTOP), δ (naltrinodole, NTI) and κ (nor-binaltorphimine, BNI) opioid receptors were administered intrathecally 10 min before each of two EA treatments at acupoint Huantiao (GB30), one immediately post and the other 2 h post-CFA. Morphine was given (i.p.) 40 min before the second EA treatment. PWL was measured before and 2.5 and 5 h post-CFA. Both 10 and 100 Hz EA-produced anti-hyperalgesia were blocked spinally by μ- and δ- but not κ-receptor antagonists. EA combined with a sub-threshold dose of morphine (2.5 mg/kg) enhanced anti-hyperalgesia additively (10 Hz EA) or synergistically (100 Hz EA) compared to that produced by each component alone. These results suggest selective involvement of μ and δ, but not κ, receptors in EA-produced anti-hyperalgesia in rats. A combined EA and opioid drug protocol may provide an improved treatment strategy for inflammatory pain. [Copyright &y& Elsevier]

Background: Electroacupuncture (EA) has been reported to produce antiedema and anti-hyperalgesia effects on inflammatory disease. However, the mechanisms are not clear. The present study investigated the biochemical mechanisms of EA anti-inflammation in a rat model. Methods: Three experiments were conducted on male Sprague-Dawley rats (n = 7–8/per group). Inflammation was induced by injecting complete Freund''s adjuvant (CFA) subcutaneously into the plantar surface of one hind paw. Experiment 1 measured plasma corticosterone (CORT) levels to see if EA regulates CORT secretion. Experiment 2 studied the effects of the adrenal gland on the therapeutic actions of EA using adrenalectomy (ADX) rats. Experiment 3 determined whether a prototypical glucocorticoid receptor antagonist, RU486, affects. EA anti-edema. EA treatment, 10 Hz at 3 mA and 0.1 ms pulse width, was given twice, for 20 min each, once immediately after CFA administration and again 2 h post-CFA. Plasma CORT levels, paw thickness, indicative of the intensity of inflammation, and paw withdrawal latency (PWL) were measured 2 h and 5 h after the CFA injection. Results: EA significantly increased plasma corticosterone levels 2 h (5 folds) and 5 h (10 folds) after CFA administration compared to sham EA control, but EA alone in naive rats and CFA alone did not induce significant increases in corticosterone. Adrenalectomy blocked EA-produced anti-edema, but not EA anti-hyperalgesia. RU486 (15 μl, 15 μg/μl), a prototypical glucocorticoid receptor antagonist, also prevented EA anti-edema. Conclusion: The data demonstrate that EA activates the adrenals to increase plasma corticosterone levels and suppress edema and suggest that EA effects differ in healthy subjects and in those with pathologies. [Copyright &y& Elsevier]

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, 6.25nmol) and κ (Nor-BIN: nor-binaltorphimine, 10nmol) opioid receptors were infused into the rostral ventromedial medulla (RVM) 10min before a 30-min EA treatment at acupoint Huantiao (GB30) 1h 30min post-CFA. PWL was measured before and 2.5 post-CFA. Both 10Hz and 100Hz 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. [Copyright &y& Elsevier]

Abstract: Although electroacupuncture (EA) is widely used to treat pain, its mechanisms have not been completely understood. The present study investigated the descending inhibitory system involvement in EA action. Inflammatory pain was induced by injecting complete Freund''s adjuvant subcutaneously into one hind paw of rats with dorsolateral funiculus lesions and sham-operated rats. EA treatment, 10 Hz at 3 mA, was given twice for 20 min each, once immediately post- and again 2 h post-Freund''s adjuvant at GB 30, at the junction of the lateral 1/3 and medial 2/3 of the distance between the greater trochanter and sacral hiatus. For sham EA control, acupuncture needles were inserted bilaterally into GB 30 without electrical or manual stimulation. Paw withdrawal latency to a noxious thermal stimulus was measured at baseline and 20 min after EA treatment. Compared to sham EA, EA significantly (P <0.05, n =9) increased withdrawal latency of the inflamed hind paws in the sham-operated rats but not in those with dorsolateral funiculus lesions, indicating that lesioning blocked EA-produced anti-hyperalgesia. EA, compared to sham EA, also significantly inhibited Fos expression in laminae I–II of the spinal cord in the sham-operated rats (58.4±6.5 vs. 35.2±5.4 per section) but not in those with dorsolateral funiculus lesions. Further, EA activated serotonin- and catecholamine-containing neurons in the nucleus raphe magnus and locus coeruleus that project to the spinal cord. The results demonstrate that EA inhibits transmission of noxious messages and hyperalgesia by activating supraspinal neurons that project to the spinal cord. [Copyright &y& Elsevier]