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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.)

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.

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.

Research supports the effectiveness of acupuncture for conditions such as chronic low back and knee pain. In a five-patient pilot study the modality also improved the symptoms of chemotherapy-induced neuropathic pain. Using an established rat model of paclitaxel-induced peripheral neuropathy, we evaluated the effect of electroacupuncture (EA) on paclitaxel-induced hyperalgesia and allodynia that has not been studied in an animal model. We hypothesize that EA would relieve the paclitaxel-induced mechanical allodynia and hyperalgesia, which was assessed 30 min after EA using von Frey filaments. Beginning on day 13, the response frequency to von Frey filaments (4-15 g) was significantly increased in paclitaxel-injected rats compared to those injected with vehicle. EA at 10 Hz significantly (P<0.05) decreased response frequency at 4-15 g compared to sham EA; EA at 100 Hz only decreased response frequency at 15 g stimulation. Compared to sham EA plus vehicle, EA at 10 Hz plus either a μ, δ, or κ opioid receptor antagonist did not significantly decrease mechanical response frequency, indicating that all three antagonists blocked EA inhibition of allodynia and hyperalgesia. Since we previously demonstrated that μ and δ but not κ opioid receptors affect EA anti-hyperalgesia in an inflammatory pain model, these data show that EA inhibits pain through different opioid receptors under varying conditions. Our data indicate that EA at 10 Hz inhibits mechanical allodynia/hyperalgesia more potently than does EA at 100 Hz. Thus, EA significantly inhibits paclitaxel-induced allodynia/hyperalgesia through spinal opioid receptors, and EA may be a useful complementary treatment for neuropathic pain patients., (Copyright © 2011 Elsevier B.V. All rights reserved.)

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., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objectives: Early life psychological stress is an essential factor contributing to the development of irritable bowel syndrome (IBS), with corticotrophin releasing factor (CRF) having been implicated in this common gastrointestinal disorder. The aim of our study is to examine the effect of neonatal maternal separation (NMS), an early life stress model, on the brain CRF expression following visceral pain induced by colorectal distension (CRD) stimuli in male rats., Methods: Male neonatal Sprague-Dawley rats were subjected to 3-hr daily maternal separation on postnatal day 2-21, with unseparated normal (N) rats serving as controls. Electromyogram signals (EMG) in response to phasic CRD were measured. The results demonstrated an increased pain response and EMG magnitudes in NMS rats as compared to N rats in response to CRD stimulation. The mRNA and protein expressions of CRF in hippocampus, cortex and thalamus of NMS and N group following the CRD stress were determined by real-time quantitative PCR and western-blotting studies respectively., Results: There was an increased mRNA and protein level of CRF in thalamus of NMS rats but no apparent change in CRF expression in hippocampus and cortex of both groups. Furthermore, an increased expression of CRF type 1 receptor (CRF-R1) was observed in the thalamus of NMS rats., Conclusion: These results suggested an up-regulation of thalamus CRF-R1 is associated with visceral hyperalgesia in the rat model of NMS.

Cancer pain impairs the quality of life of cancer patients, but opioid intervention can cause significant side effects that further decrease quality of life. Although electroacupuncture (EA) has been used to treat cancer pain, its mechanisms are largely unknown. To examine its effects and underlying mechanisms on cancer pain, we injected AT-3.1 prostate cancer cells into the tibia to induce bone cancer in the male Copenhagen rat. The resulting pain was treated with 10Hz/2mA/0.4ms pulse EA for 30min daily at the point equivalent to the human acupoint GB30 (Huantiao) between days 14 and 18 after the injection. For sham control, EA needles were inserted into GB30 without stimulation. Thermal hyperalgesia, a decrease in paw withdrawal latency (PWL) to a noxious thermal stimulus, and mechanical hyperalgesia, a decrease in paw withdrawal pressure threshold (PWPT), was measured at baseline and 20min after the EA treatment. Preprodynorphin mRNA and dynorphin were determined by RT-PCR and immunohistochemistry, respectively. Thermal and mechanical hyperalgesia developed ipsilaterally between days 12 and 18 after cancer cell inoculation. EA significantly (P<0.05) attenuated this hyperalgesia, as shown by increased PWL and PWPT, and inhibited up-regulation of preprodynorphin mRNA and dynorphin compared to sham control. Intrathecal injection of antiserum against dynorphin A (1-17) also significantly inhibited the cancer-induced hyperalgesia. These results suggest that EA alleviates bone cancer pain at least in part by suppressing dynorphin expression, and they support the clinical use of EA in the treatment of cancer pain.

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.

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.

It is known that interleukin-1beta facilitates pain, but the mechanisms of this are not understood. This study investigated the role of interleukin-1beta in the expression of Fos, a marker of neuronal activation, and hyperalgesia caused by injecting complete Freund's adjuvant into one hind paw of the rat. Interleukin-receptor antagonist (interleukin-1ra, 0.005 mg/rat) was given intrathecally twice, 24 h before complete Freund's adjuvant and immediately before complete Freund's adjuvant injection, to block interleukin-1beta action. Fos expression was measured 2 h after complete Freund's adjuvant injection. Paw withdrawal latency was used to assess hyperalgesia. The findings were that interleukin-1ra inhibited inflammation-induced Fos expression and hyperalgesia, which suggests that endogenous interleukin-1beta facilitates transmission of noxious messages at the spinal level by processes involving an enhanced Fos expression.

Chinese herbal medicine has been used for thousands of years in China and other Asian countries to treat a variety of inflammatory diseases. The classic Chinese herbal formula, Huo Luo Xiao Ling Dan (HLXL) is commonly used in traditional Chinese herbal medicine for the treatment of joint pain and other symptoms of arthritis. The present study is an investigation of the effects of a modified HLXL extract on persistent hyperalgesia and edema in rats with peripheral inflammation. Inflammation was induced by injecting complete Freund's adjuvant (CFA) into one hind paw. Four dosages of the extract were compared to a vehicle control. Each was administered intragastrally (i.g.) daily for seven days beginning one day before CFA. Hyperalgesia was assessed using a paw withdrawal latency (PWL) test and edema was determined by measuring paw thickness at pre-CFA and 2 hours, 24 hours, and 5 days post-CFA. Immunohistochemistry was performed 2 hours post-CFA to determine spinal Fos protein expression. Adverse effects of the extract were monitored by observing the animals closely for unusual behavioral changes. Compared to the control, HLXL at the two lower dosages (0.575 g/kg and 1.15 g/kg) were effective in the later stage (day 5) of inflammatory hyperalgesia and edema, while the two higher dosages (2.3 g/kg and 4.6 g/kg) alleviated early stage hind paw inflammation and hyperalgesia and facilitated recovery from paw edema and hyperalgesia during the late stage. HLXL at 2.30 g/kg significantly suppressed Fos expression in laminae I-II, III-IV and V-VI ipsilaterally and in III-IV contralaterally. No significant signs of toxicity or adverse effects were observed. The data suggest that HLXL dosage-dependently attenuates CFA-induced inflammation and hyperalgesia, at least in part by inhibiting noxious transmission at the dorsal horn of the spinal cord.

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.

Previous studies showed that electroacupuncture (EA) significantly attenuates inflammatory hyperalgesia in a complete Freund's adjuvant (CFA)-induced inflammatory pain rat model. The present study demonstrates that pretreatment with Derm-sap, a selective toxin for neurons that contain mu opioid receptor (MOR), specifically decreases MOR and blocks EA anti-hyperalgesia. These data suggest that spinal MOR-containing neurons are involved in the processes by which EA produces anti-hyperalgesia.

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.

Our previous study showed that electroacupuncture (EA), an adjuvant to conventional medicine, significantly attenuated hyperalgesia in a rat model of inflammatory pain. In the present study, we evaluated the potential additive and/or synergism of EA and a sub-effective dose of dizocilpine maleate (MK-801), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, on hyperalgesia in the same rat model of inflammatory pain. Hyperalgesia, manifesting as decreased paw withdrawal latency (PWL) to a noxious stimulus, was induced by injecting complete Freund's adjuvant (CFA) into the plantar surface of one hind paw of each rat. EA treatments were given at acupoint GB30 immediately after and 2 h after CFA. MK-801 at 0.001 mg/rat was given (i.t.) 10 min before each of the two EA treatments. PWL was measured prior to and 2.5 and 5 h post-CFA. Ten and 100 Hz EA significantly inhibited CFA-induced hind paw hyperalgesia. Both 10 and 100 Hz EA combined with the sub-effective dose of 0.001 mg/rat MK-801 showed prolonged anti-hyperalgesia with no side effects. These results demonstrate that EA combined with a sub-effective dose of this NMDA receptor antagonist enhances anti-hyperalgesia, and this combination may provide an effective strategy for pain management.

Objective: Ruxiang, or Gummi olibanum, an herbal medicine derived from the gum resin of Boswellia carterii Birdw. (BC) of the family Burseraceae, has been used traditionally in China to alleviate pain and reduce inflammation. The present study is an investigation of the effects of a BC extract on persistent hyperalgesia and edema in rats with peripheral inflammation., Design: In this randomized, blinded study, the antihyperalgesic and antiedema effects of 3 dosages of BC were compared to a vehicle control. Inflammation was induced in rats by injecting complete Freund's adjuvant (CFA) into one hind paw. A single oral dose of the BC extract was administered daily for 7 days, beginning one day before CFA. Hyperalgesia was assessed using a paw withdrawal latency (PWL) test pre-CFA and 2 hours, 5 hours, 1 day, and 5 days post-CFA. Edema was determined by measuring paw thickness at the same time points. Spinal Fos protein expression was analyzed 2 hours post-CFA. Adverse effects of the extract were monitored by observing the animals closely for unusual behavioral changes., Results: Compared to control, a dosage of 0.45 g/kg BC significantly lengthened PWL and reduced paw edema on day 5 post-CFA. At 0.90 g/kg, BC significantly lengthened PWL at 5 hours, 1 day, and 5 days, and reduced paw edema at 2 hours, 5 hours, 1 day, and 5 days. This dosage also significantly suppressed spinal Fos expression in the medial half of laminae I-II. At 1.80 g/kg, BC significantly lengthened PWL and reduced paw edema at all time points. No noticeable adverse effects were observed in animals given the lower dosages of BC, but adverse effects in some animals were observed at 1.80 g/kg per day. In the acute toxicity study, the maximal single dose of 2.50 g/kg produced no adverse effects in the treated rats during the 14 days of observation., Conclusions: The data suggest that BC produces significant antihyperalgesia and anti-inflammation effects and that the antihyperalgesia may be mediated by suppressed inflammation-induced Fos expression in the spinal dorsal horn neurons.

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.

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 mu and delta opioid receptors at 2-15 Hz and by kappa 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 mu (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH2, CTOP), delta (naltrinodole, NTI) and kappa (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 mu- and delta- but not kappa-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 mu and delta, but not kappa, receptors in EA-produced anti-hyperalgesia in rats. A combined EA and opioid drug protocol may provide an improved treatment strategy for inflammatory pain.

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.)

Glucocorticoids (GC) play important roles in response to stressful stimuli, including pain. This study examined the effects of bilateral adrenalectomy (ADX) and dexamethasone (DEX) replacement on the hyperalgesia and spinal preprodynorphin (PPD) mRNA expression induced by injecting complete Freund's adjuvant (CFA) into rats' hind paws. The results demonstrated that CFA induced more intense hyperalgesia and up-expression of spinal PPD mRNA in ADX rats than in control rats, while both of these intensified reactions could be significantly suppressed by subcutaneous pretreatment with DEX. This leads to the conclusion that both exogenous (pharmacological) and endogenous (physiological) GC suppresses the behavioral hyperalgesia and the up-regulation of spinal PPD mRNA induced by sustained peripheral inflammation. The results also suggest that spinal PPD mRNA suppression may partially underlie the inhibition of behavioral hyperalgesia.

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.

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]

The experience of pain is highly variable among individuals, which may be due in part to the effects of genetic factors on the central transmission and modulation of noxious inputs. This study examined behavioral responses and the expression of preprodynorphin (PPD) mRNA at the spinal level during complete Freund''s adjuvant-induced inflammation of the unilateral hind paw in male Fischer 344 (F344), Sprague–Dawley (SD), and Lewis (LEW) rats. Experiments showed that F344 rats exhibited stronger hind paw hyperalgesia and greater spinal PPD mRNA induction than SD or LEW rats. These results indicate that genetic factors that determine the spinal PPD mRNA and dynorphin production underlie strain-dependent differences in pain perception. [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: 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. [Copyright &y& Elsevier]

Abstract: Studies suggest that astrocytes and microglia in the spinal cord are involved in the development of persistent pain induced by tissue inflammation and nerve injury. However, the role of glial cells in bone cancer pain is not well understood. The present study evaluated the spinal glial activation in a novel rat model of bone cancer pain produced by injecting AT-3.1 prostate cancer cells into the unilateral tibia of male Copenhagen rats. The structural damage to the tibia was monitored by radiological analysis. The thermal hyperalgesia, mechanical hyperalgesia and allodynia, and spontaneous flinch were measured. The results showed that: (1) inoculation of prostate cancer cells, but not the vehicle Hank''s solution, induced progressive bone destruction at the proximal epiphysis of the tibia from day 7–20 post inoculation; (2) the inoculation also induced progressive thermal hyperalgesia, mechanical hyperalgesia, mechanical allodynia, and spontaneous flinches; (3) astrocytes and microglia were significantly activated in the spinal cord ipsilateral to the cancer leg, characterized by enhanced immunostaining of both glial fibrillary acidic protein (GFAP, astrocyte marker) and OX-42 (microglial marker); (4) IL-1β was up-regulated in the ipsilateral spinal cord, evidenced by an increase of IL-1β immunostained astrocytes. These results demonstrate that injection of AT-3.1 prostate cancer cells into the tibia produces progressive hyperalgesia and allodynia associated with the progression of tibia destruction, indicating the successful establishment of a novel male rat model of bone cancer pain. Further, bone cancer activates spinal glial cells, which may release IL-1β and other cytokines and contribute to hyperalgesia. [Copyright &y& Elsevier]