Electroacupuncture at Neurogenic Spots in Referred Pain Areas Attenuates Hepatic Damages in Bile Duct-Ligated Rats.

Visceral pain frequently produces referred pain at somatic sites due to the convergence of somatic and visceral afferents. In skin overlying the referred pain, neurogenic spots characterized by hyperalgesia, tenderness and neurogenic inflammation are found. We investigated whether neurogenic inflammatory spots function as acupoints in the rat model of bile duct ligation-induced liver injury. The majority of neurogenic spots were found in the dorsal trunk overlying the referred pain and matched with locations of acupoints. The spots, as well as acupoints, showed high electrical conductance and enhanced expression of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP). Electroacupuncture at neurogenic spots reduced serum hepatocellular enzyme activities and histological patterns of acute liver injury in bile duct ligation (BDL) rats. The results suggest that the neurogenic spots have therapeutic effects as acupoints on hepatic injury in bile-duct ligated rats.

[Effects of Suspending Moxibustion at "Dazhui" (GV 14) on Neurogenic Inflammation in Asthma Rats].

OBJECTIVE: To observe the effect of suspending-moxibustion stimulation of "Dazhui" (GV 14) with different quantities on the levels of nerve growth factor(NGF) , substance P(SP) , calcitonin gene-related peptide (CGRP), neurokinin A (NKA) , neurokinin B (NKB) and phosphorylated extracellular signal-regulated kinases (pERK) in the bronchoalveolar lavage fluid (BALF) of asthma rats, so as to analyze its mechanisms underlying improving asthma. METHODS: Sixty male SD rats were randomly divided into six groups: blank control, model, 15 min-moxibustion (15 min-moxi), 30 min-moxi, 60 min-moxi and 90 min-moxi (n = 10 rats in each group). The asthma model was established by intraperitoneal injection of suspension of egg protein, magaldrate, and inactivated Bacillus pertussis (on day 1 and 8), and inhaling the atomized ovalbumin saline (from day 15 on for 14 days). Mild moxibustion was conducted at "Dazhui" (GV 14) for 15 min, 30 min, 60 min and 90 min, respectively, once daily for 7 days. The levels of NGF, SP, CGRP, NKA, NKB, and pERK in the BALF were detected by ELISA (enzyme-linked immuno sorbent assay). RESULTS: The contents of NGF, SP, CGRP, NKA, NKB and pERK in the BALF in the model group were obviously higher than those in the blank control group (P < 0.01), suggesting an apparent inflammatory reaction in rats after modeling. Following moxibustion, the levels of NGF, SP, CGRP, NKA, NKB and pERK of the four treatment groups were significantly down-regulated compared with the model group (P < 0.01). The effect of 30 min-moxi group was obviously superior to that of 15 min-moxi group (P < 0.01), and those of 60 min-moxi and 90 min-moxi groups were markedly superior to those of 15 min-moxi and 30 min-moxi groups (P < 0.01) in down-regulating NGF, SP, CGRP, NKA, NKB, and pERK levels in the BALF. No significant differences were found between the 60 min-moxi and 90 min-moxi groups in down-regulating NGF, SP, CGRP, NKA, NKB, and pERK levels (P > 0.05). CONCLUSION: Suspending-moxibustion stimulation of GV 14 can down-regulate the contents of NGF, SP, CGRP, NKA, NKB, and pERK levels in the BALF in asthma rats, suggesting a relief of neurogenic inflammation reaction after moxibustion. The effect of moxibustion presents a time-dependant manner and peaks at 60 min.

Rostral ventromedial medulla µ, but not κ, opioid receptors are involved in electroacupuncture anti-hyperalgesia in an inflammatory pain rat model.

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.

Anti-inflammatory effects of electronic signal treatment.

Inflammation often plays a key role in the perpetuation of pain. Chronic inflammatory conditions (e.g. osteoarthritis, immune system dysfunction, micro-circulatory disease, painful neuritis, and even heart disease) have increased as baby boomers age. Medicine's current anti-inflammatory choices are NSAIDs and steroids; the value in promoting cure and side effect risks of these medications are unclear and controversial, especially considering individual patient variations. Electricity has continuously been a powerful tool in medicine for thousands of years. All medical professionals are, to some degree, aware of electrotherapy; those who directly use electricity for treatment know of its anti-inflammatory effects. Electronic signal treatment (EST), as an extension of presently available technology, may reasonably have even more anti-inflammatory effects. EST is a digitally produced alternating current sinusoidal electronic signal with associated harmonics to produce theoretically reasonable and/or scientifically documented physiological effects when applied to the human body. These signals are produced by advanced electronics not possible even 10 to 15 years ago. The potential long-lasting anti-inflammatory effects of some electrical currents are based on basic physical and biochemical facts listed in the text below, namely that of stimulating and signaling effective and long-lasting anti-inflammatory effects in nerve and muscle cells. The safety of electrotherapeutic treatments in general and EST in particular has been established through extensive clinical use. The principles of physics have been largely de-emphasized in modern medicine in favor of chemistry. These electrical treatments, a familiar application of physics, thus represent powerful and appropriate elements of physicians' pain care armamentaria in the clinic and possibly for prescription for use at home to improve overall patient care and maintenance of quality of life via low-risk and potentially curative treatments.

The role of the intensity of low frequency electroacupuncture stimulation on the modulation of capsaicin-induced edema in the rat paw. A blind controlled study.

Experimental animal and clinical human data suggest that electroacupuncture (EAP) reduces the release of substance P from sensitive neurons, both at medullar level and in the periphery. Aim of our study is to verify the effect of different intensities of stimulation on edema induced by subcutaneous administration of capsaicin. The study was performed on 72 male Sprague-Dawley rats divided into 4 experimental groups according to the intensity of electrostimulation (5, 10, 50, 70 mA) and a control group. A constant current electrical stimulator delivering positive and negative biphasic wave (duration of one pulse wave complex: 500 microsec; pulse repetition rate: 5/sec) has been used for the stimulation. The lowest intensity of stimulation (5 mA) was effective in the prevention of neurogenic edema. Conversely, higher stimulation intensities, namely 10 and 50 mA, were not effective in reducing edema. Stimulation at 70 mA caused a worsening of edema, probably due to an increased release of substance P in the paw.

The effect of sensory nerve stimulation on sensory nerve function in people with peripheral neuropathy associated with diabetes.

OBJECTIVE: To assess the effect of sensory nerve stimulation in older people with peripheral neuropathy associated with diabetes (DPN). MATERIALS AND METHODS: A randomized, placebo controlled, double blind trial was used to assess the effect of 12 weeks of low frequency sensory nerve stimulation (LF-SNS) in the lower limb [International Patent Application No. PCT/AU2004/001079: 'nerve function and tissue healing' (Z. Khalil)]. Response to capsaicin, basal microvascular blood flow, electric cutaneous threshold and oxygen tension were assessed pre- and post-treatment and between limbs. PARTICIPANTS: People 55 years of age or older diagnosed with DPN: 35 active and 31 placebo participants. RESULTS: Between groups comparisons: no significant differences occurred between stimulation groups. Within subject comparisons: in the active LF-SNS group, comparing stimulated to contralateral legs, there were significant increases in size of capsaicin flare [t(1,33)=3.65, p<0.05] and capillary blood flow [t(1,34)=-0.33, p<0.05]. There was a trend to improvement in time to initial flare response [t(1,34)=-1.86, p=0.07]. No changes were evident in the placebo group. RESPONDER ANALYSES: In a group of 'responders', the time to initial flare response (p<0.05, r=0.64), size of capsaicin flare (p<0.05 r=1.0) and microvascular blood flow (p<0.05, r=0.60) improved significantly after LF-SNS. CONCLUSIONS: The observed data suggest that LF-SNS improves nerve function in a subset of people with DPN. Targeting toward probably 'responders' may deliver the greatest benefit from short-term therapy. Testing optimal application in others seems warranted.

Vagus nerve stimulation suppresses pain but has limited effects on neurogenic inflammation in humans.

Left vagus nerve stimulation reduces pain perception in humans. In animal studies it has been shown that beyond the inhibitory effect, which the vagus nerve exerts via its widespread central connections, there might be also a peripheral effect on nociceptors. In humans, the exact mechanisms of VNS-mediated analgesia are still unclear. To test whether VNS also affects activation of primary nociceptive afferents in humans, we investigated 11 patients before and after implantation of a vagus nerve stimulator by using tonic pressure as pain stimulus. Vasodilator axon reflexes ("neurogenic" inflammation) were quantified by laser-Doppler-imaging and served as surrogates for primary afferent activation. Pain was measured on a visual analogue scale (VAS). The squeezing experiment was performed three times at 15 min intervals in each session. As controls 9 healthy age- and gender-matched subjects were studied. As shown in our previous study, VNS significantly reduces pain to tonic pressure. Likewise, there was a moderate reduction of the blood flow within the area of the axon reflex, which indicates a possible but limited inhibitory effect of VNS on peripheral nociceptors. Our data suggests that VNS might affect peripheral nociceptor function in humans. Since VNS has been shown to be more effective in experimental procedures in which pain magnitude is amplified by central processing, further studies are warranted to elucidate whether the central or peripheral effect is most important for VNS-mediated analgesia.

Electroacupuncture attenuates inflammation in a rat model.

BACKGROUND: 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, and the underlying mechanisms of acupuncture-produced anti-inflammation are unclear. OBJECTIVE: To evaluate the effectiveness of electroacupuncture (EA) on inflammation in a rat model. MATERIALS AND METHODS: Four experiments were conducted on male Sprague-Dawley rats (n = 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 immobilization on such stress indicators as heart rate and blood pressure. RESULTS: 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. CONCLUSION: At 10 Hz but not 100 Hz, EA suppresses inflammation by activating the hypothalamus-pituitary-adrenal axis (HPA) and the nervous system.

Analgesic profile of intrathecal P2X(3) antisense oligonucleotide treatment in chronic inflammatory and neuropathic pain states in rats.

Extracellular adenosine triphosphate (ATP), acting at P2X ionotropic receptors, is implicated in numerous sensory processes. Exogenous ATP has been shown to be algogenic in both animals and humans. Research focus has been directed towards the P2X(3) receptor, as it is preferentially expressed on nociceptive C-fibers and its implication in pain processing is supported by an altered nociceptive phenotype in P2X(3) knock-out mice. In order to further characterize the role of P2X(3) receptor activation in nociception, we evaluated the effects of continuous intrathecal administration of P2X(3) antisense oligonucleotides for 7 days in the rat. P2X(3) receptor antisense oligonucleotide treatment significantly decreased nociceptive behaviors observed after injection of complete Freund's adjuvant (CFA), formalin or alphabeta-methylene ATP into the rat's hind paw. The anti-hyperalgesic effects of the antisense treatment in the CFA model of inflammatory pain were dose related. Similar effects were observed with two distinct P2X(3) antisense oligonucleotides. These behavioral effects were significantly correlated with a decrease in P2X(3) receptor protein expression in the dorsal root ganglia (DRG). In contrast, a decrease in P2X(3) receptor protein expression in the DRG did not affect nociceptive behavior in the carrageenan model of acute thermal hyperalgesia. P2X(3) receptor antisense oligonucleotide treatment also significantly reduced mechanical allodynia observed after spinal nerve ligation. Overall, the present data demonstrate that activation of P2X(3) receptors contribute to the expression of chronic inflammatory and neuropathic pain states and that relief form these forms of chronic pain might be achieved by selective blockade of P2X(3 )receptor expression or activation.

Acupuncture modulation of capsaicin-induced inflammation: effect of intraperitoneal and local administration of naloxone in rats. A blinded controlled study.

OBJECTIVE: It is believed that acupunctural stimulation induces an analgesic response mainly through a central mechanism: that is, through an increase in the production of opioid peptides and their release at different levels in the nervous system. We sought to establish whether the modulating effect of acupuncture on experimental neurogenic edema can be attributed to a central mechanism only or whether a peripheral mechanism could also exist. Intraperitoneal administration was compared to local administration in the same paw in rats that were injected with capsaicin and in the same dermatome of the acupunctural stimulation. MATERIALS AND METHODS: Experimentation was conducted on 105 male Sprague-Dawley rats weighing 180-220 g, divided into 7 groups as follows: group 1, control; groups 2-4 (15 animals), stimulated with manual acupuncture; group 3 also treated with intraperitoneal naloxone 1 mg/kg; group 4 also treated locally with naloxone (20 microg); groups 5-7 (15 animals), stimulated with 5 Hz and 5 mA electroacupuncture (EAP); group 6 also treated with intraperitoneal naloxone, 1 mg/kg, group 7 also treated locally with naloxone (20 microg). RESULTS: The results indicate that the administration of 1 mg/kg of naloxone intraperitoneally can inhibit the modulating effect of acupunctural stimulation. Equally effective in inhibiting the modulating effect of acupunctural stimulation, although not having a systemic effect, is a 20-microg dose of naloxone administered peripherally on the site of edema induction. CONCLUSION: It is possible to conclude that both systemic and peripheral mechanisms seem to be implicated in the modulating effect of acupuncture on the neurogenic inflammation mechanism.

The effects of parachlorophenylalanine and naloxone on acupuncture and electroacupuncture modulation of capsaicin-induced neurogenic edema in the rat hind paw. A controlled blind study.

OBJECTIVE: The aim of this work was to study the effect of pre-treatment with parachlorophenylalanine (PCPA) and posttreatment with naloxone on the modulating action on neurogenic inflammation of manual acupuncture and low intensity (5 mAmp), low frequency (5 Hz) electroacupuncture (EA). METHODS: Edema was induced by the subcutaneous administration of 50 micrograms capsaicin in rat paws. Pre-treatment with intraperitoneal PCPA was given for 3 days: 200 mg/Kg on the first day and 100 mg/Kg on the second and third days. Naloxone (1 mg/Kg) was administered at the end of the stimulation. RESULTS: The results show that naloxone and PCPA reduce the anti-edema effect of both manual acupuncture and EA. Combined administration of the two drugs completely eliminated the effect of manual acupuncture, and decreased but did not abolish the effect of electroacupuncture. CONCLUSION: These results indicate that both the opioid and the serotonergic inhibitory control systems are involved in the modulating action of acupunctural stimulation on neurogenic inflammation.