Electroacupuncture alleviates chemotherapy-induced pain through inhibiting phosphorylation of spinal CaMKII in rats.

BACKGROUND: Current medical treatments for chemotherapy-induced pain (CIP) are either ineffective or have adverse side effects. Acupuncture may alleviate CIP, but its effectiveness against this condition has not been studied. Paclitaxel causes neuropathic pain in cancer patients. METHODS: We evaluated the effects of electroacupuncture (EA) on paclitaxel-induced CIP in a rat model. Paclitaxel (2 mg/kg) or vehicle was injected (i.p.) on alternate days of 0-6. The resulting pain was treated with 10 Hz/2 mA/0.4 ms pulse EA for 30 min at the equivalent of human acupoint GB30 (Huantiao) once every other day between days 14 and 26. For sham control, EA needles were inserted into GB30 without stimulation. Von Frey filaments with bending forces of 2-8 g and 15 g were used to assess mechanical allodynia and hyperalgesia, respectively, on day 13 and once every other day between 14-26 days and then for 2-3 weeks after EA treatment. RESULTS: Compared to sham control, EA significantly alleviated paclitaxel-induced mechanical allodynia and hyperalgesia, as shown by less frequent withdrawal responses to the filaments. The alleviation of allodynia/hyperalgesia lasted up to 3 weeks after the EA treatment. EA significantly inhibited phosphorylation of Ca2+ /calmodulin-dependent protein kinase II (CaMKII) in the spinal cord. KN-93, a selective inhibitor of p-CaMKII, inhibited mechanical allodynia/hyperalgesia and p-CaMKII. 5-HT1A receptor antagonist blocked EA inhibition of allodynia/hyperalgesia and p-CaMKII. CONCLUSIONS: Electroacupuncture activates 5-HT 1A receptors in the spinal cord and inhibits p-CaMKII to alleviate both allodynia and hyperalgesia. The data support acupuncture/EA as a complementary therapy for CIP. SIGNIFICANCE: Electroacupuncture (EA) activates spinal 5-HT1A receptors to inhibit p-CaMKII to alleviate paclitaxel-induced pain. Acupuncture/EA may be used as a complementary therapy for CIP.

Genetic variants in adiponectin and blood pressure responses to dietary sodium or potassium interventions: a family-based association study.

Previous studies have shown that genetic factors might have an important role in blood pressure (BP) responses to dietary salt or potassium intake. The aim of this study was to assess the association of common genetic variants of the adiponectin gene with BP responses to controlled dietary sodium or potassium interventions. Subjects (n=334) from 124 families in rural areas of Northern China were recruited. After a 3-day baseline observation, participants sequentially maintained a 7-day low-sodium diet (NaCl, 3 g per day; or sodium, 51.3 mmol per day), followed by a 7-day high-sodium diet (NaCl, 18 g per day; or sodium, 307.8 mmol per day) and a 7-day high-sodium plus potassium supplementation intervention (KCl, 4.5 g per day; or potassium, 60 mmol per day). A total of seven single nucleotide polymorphisms (SNPs) in the adiponectin gene were selected as the study sites. After adjustment for multiple testing, the adiponectin SNP rs16861205 was significantly associated with the diastolic BP (DBP) response to low-salt intervention, and the DBP and mean arterial pressure (MAP) responses to high-salt intervention (P=0.028, 0.023 and 0.027, respectively). SNP rs822394 was associated with the DBP and MAP responses to low-salt intervention and the DBP response to high-salt intervention (P=0.023, 0.030 and 0.033 respectively). Meanwhile, significant association also existed between SNP rs16861194 and the systolic BP response to potassium supplementation intervention (P=0.026). In addition, SNP rs822394 was significantly associated with basal DBP after adjustment for multiple testing (P=0.033). Our study indicated that the genetic polymorphisms in the adiponectin gene are significantly associated with BP responses to dietary sodium and potassium intake.

Effect of salt intake and potassium supplementation on brachial-ankle pulse wave velocity in Chinese subjects: an interventional study

Accumulating evidence has suggested that high salt and potassium might be associated with vascular function. The aim of this study was to investigate the effect of salt intake and potassium supplementation on brachial-ankle pulse wave velocity (PWV) in Chinese subjects. Forty-nine subjects (28-65 years of age) were selected from a rural community of northern China. All subjects were sequentially maintained on a low-salt diet for 7 days (3.0 g/day NaCl), a high-salt diet for an additional 7 days (18.0 g/day NaCl), and a high-salt diet with potassium supplementation for a final 7 days (18.0 g/day NaCl+4.5 g/day KCl). Brachial-ankle PWV was measured at baseline and on the last day of each intervention. Blood pressure levels were significantly increased from the low-salt to high-salt diet, and decreased from the high-salt diet to high-salt plus potassium supplementation. Baseline brachial-ankle PWV in salt-sensitive subjects was significantly higher than in salt-resistant subjects. There was no significant change in brachial-ankle PWV among the 3 intervention periods in salt-sensitive, salt-resistant, or total subjects. No significant correlations were found between brachial-ankle PWV and 24-h sodium and potassium excretions. Our study indicates that dietary salt intake and potassium supplementation, at least in the short term, had no significant effect on brachial-ankle PWV in Chinese subjects.

Effect of salt intake and potassium supplementation on brachial-ankle pulse wave velocity in Chinese subjects: an interventional study.

Accumulating evidence has suggested that high salt and potassium might be associated with vascular function. The aim of this study was to investigate the effect of salt intake and potassium supplementation on brachial-ankle pulse wave velocity (PWV) in Chinese subjects. Forty-nine subjects (28-65 years of age) were selected from a rural community of northern China. All subjects were sequentially maintained on a low-salt diet for 7 days (3.0 g/day NaCl), a high-salt diet for an additional 7 days (18.0 g/day NaCl), and a high-salt diet with potassium supplementation for a final 7 days (18.0 g/day NaCl+4.5 g/day KCl). Brachial-ankle PWV was measured at baseline and on the last day of each intervention. Blood pressure levels were significantly increased from the low-salt to high-salt diet, and decreased from the high-salt diet to high-salt plus potassium supplementation. Baseline brachial-ankle PWV in salt-sensitive subjects was significantly higher than in salt-resistant subjects. There was no significant change in brachial-ankle PWV among the 3 intervention periods in salt-sensitive, salt-resistant, or total subjects. No significant correlations were found between brachial-ankle PWV and 24-h sodium and potassium excretions. Our study indicates that dietary salt intake and potassium supplementation, at least in the short term, had no significant effect on brachial-ankle PWV in Chinese subjects.

Electroacupuncture inhibition of hyperalgesia in an inflammatory pain rat model: involvement of distinct spinal serotonin and norepinephrine receptor subtypes.

BACKGROUND: Although acupuncture analgesia is well documented, its mechanisms have not been thoroughly clarified. We previously showed that electroacupuncture (EA) activates supraspinal serotonin- and norepinephrine-containing neurones that project to the spinal cord. This study investigates the involvement of spinal alpha(2)-adrenoceptors (α2-ARs) and 5-hydroxytryptamine (serotonin) receptors (5-HTRs) in EA effects on an inflammatory pain rat model. METHODS: Inflammatory hyperalgesia was induced by injecting complete Freund's adjuvant (CFA, 0.08 ml) into the plantar surface of one hind paw and assessed by paw withdrawal latency (PWL) to a noxious thermal stimulus. The selective α2a-AR antagonist BRL-44408, α2b-AR antagonist imiloxan hydrochloride, 5-HT2B receptor (5-HT2BR) antagonist SB204741, 5-HT3R antagonist LY278584, or 5-HT1AR antagonists NAN-190 hydrobromide, or WAY-100635 were intrathecally administered 20 min before EA or sham EA, which was given 2 h post-CFA at acupoint GB30. RESULTS: EA significantly increased PWL compared with sham [7.20 (0.46) vs 5.20 (0.43) s]. Pretreatment with α2a-AR [5.35 (0.45) s] or 5-HT1AR [5.22 (0.38) s] antagonists blocked EA-produced anti-hyperalgesia; α2b-AR, 5-HT2BR, and 5-HT3R antagonist pretreatment did not. Sham plus these antagonists did not significantly change PWL compared with sham plus vehicle, indicating that the antagonists had little effect on PWL. Immunohistochemical staining demonstrated that α2a-ARs are on primary afferents and 5-HT1ARs are localized in N-methyl-d-aspartic acid (NMDA) subunit NR1-containing neurones in the spinal dorsal horn. CONCLUSIONS: The data show that α2a-ARs and 5-HT1ARs are involved in the EA inhibition of inflammatory pain and that the NMDA receptors are involved in EA action.

Electroacupuncture alleviates affective pain in an inflammatory pain rat model.

Pain has both sensory-discriminative and emotional-affective dimensions. Previous studies demonstrate that electroacupuncture (EA) alleviates the sensory dimension but do not address the affective. An inflammatory pain rat model, produced by a complete Freund adjuvant (CFA) injection into the hind paw, was combined with a conditioned place avoidance (CPA) test to determine whether EA inhibits spontaneous pain-induced affective response and, if so, to study the possibility that rostral anterior cingulate cortex (rACC) opioids underlie this effect. Male Sprague-Dawley rats (250-275 g, Harlan) were used. The rats showed place aversion (i.e. affective pain) by spending less time in a pain-paired compartment after conditioning than during a preconditioning test. Systemic non-analgesic morphine (0.5 and 1.0 mg/kg, i.p.) inhibited the affective reaction, suggesting that the affective dimension is underpinned by mechanisms different from those of the sensory dimension of pain. Morphine at 0.5 and at 1 mg/kg did not induce reward. Rats given EA treatment before pain-paired conditioning at GB 30 showed no aversion to the pain-paired compartment, indicating that EA inhibited the affective dimension. EA treatment did not produce reward or aversive effect. Intra-rACC administration of D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP), a selective mu opioid receptor antagonist, but not norbinaltorphimine (nor-BNI), a selective kappa opioid receptor antagonist, blocked EA inhibition of the affective dimension. These data demonstrate that EA activates opioid receptors in the rACC to inhibit pain-induced affective responses and that EA may be an effective therapy for both the sensory-discriminative and the affective dimensions of pain.

Electro-acupuncture attenuates behavioral hyperalgesia and selectively reduces spinal Fos protein expression in rats with persistent inflammation.

This study examined the effect of electro-acupuncture (EA) on persistent inflammatory hyperalgesia in a rat model. Inflammation and hyperalgesia were induced by injecting complete Freund's adjuvant (CFA) into one hindpaw of the rat. Hyperalgesia was determined by a decrease in paw withdrawal latencies (PWL) to a noxious thermal stimulus. EA was applied bilaterally at the acupuncture point Huantiao (G30) at the rat's hindlimbs. EA-treated rats (n = 11) had significantly longer PWLs as compared with placebo control rats (n = 7) in the inflamed paw at 2.5 hours and 5 days after injection of CFA (P <.05) and longer PWLs as compared to sham control rats (n = 9) at 2.5 hours (P >.05). Paw edema was significantly reduced in EA-treated rats versus placebo controls at 24 hours after inflammation (P <.01). Inflammation-induced spinal Fos expression in the medial half of laminae I-II in EA-treated rats versus placebo rats (n = 5 per group) was significantly reduced (P <.01). These data showed that EA delayed the onset and facilitated the recovery of inflammatory hyperalgesia and suppressed the inflammation-induced spinal Fos expression in neurons (laminae I-II) involved in receiving noxious stimulation. This rat model of persistent pain and inflammation seems to be an ideal animal model for studying the effect of acupuncture.

Dorsal column-thalamic pathway is involved in thalamic hyperexcitability following peripheral nerve injury: a lesion study in rats with experimental mononeuropathy.

A total of 68 neurons were recorded from the ventro-postero-lateral nucleus of thalamus (VPL) in rats with a unilateral chronic constriction injury (CCI) of the sciatic nerve (n=20), sham operation (n=24) and naive rats (n=24), and effects of the lesion of dorsal column (DC) pathway [DC lesion or DC+gracile nucleus lesions] on VPL nucleus neuronal activities were studied. In the VPL nucleus contralateral to the CCI (receiving input from the injured nerve), response latencies of low threshold mechanoreceptive (LTM) and wide dynamic range (WDR) neurons to electrical stimulation of the sciatic nerve were significantly longer than that in the contralateral VPL nucleus receiving input from the sham-operated side (P<0.05). In contrast, response latencies of LTM and WDR neurons to DC stimulation were not different between the sham operated and CCI sides (0.05). Background activity of WDR neurons was significantly higher in the VPL nucleus contralateral to the CCI side when compared to neurons in the VPL nucleus contralateral to the sham operated side and in naive animals. Responses of LTM and WDR neurons to innocuous mechanical stimulation of the receptive fields were significantly decreased after DC and DC+gracile nucleus lesions in all animals. However, the responses of WDR neurons to noxious stimuli were selectively reduced only in rats with CCI by DC and DC+gracile nucleus lesions (P<0.05). The decrease in noxious stimulus-evoked responses of WDR neurons in the VPL nucleus contralateral to the CCI side after DC and DC+gracile nucleus lesions was greater than that in the VPL nucleus contralateral to the sham operated side and naive animals. These results indicated that DC and DC+gracile nucleus lesions produced selective and stronger effect on noxious responses of VPL nucleus WDR neurons receiving input from the site of nerve injury. The findings suggest that the gracile nucleus-thalamic pathway conveys, or modulates, nociceptive information to the VPL nucleus following peripheral nerve injury, resulting in an increase in VPL nucleus response to noxious stimuli that contributes to the development of mechanical hyperalgesia.

[Effects of different training methods on cardiovascular autonomic regulation during bedrest].

Objective. To investigate the effects of different training methods on cardiovascular autonomic regulation under bedrest. Method. 15 healthy male volunteers aged 19-22 participated tests in head-down tilt (HDT) -6 degrees bedrest in order to observe the changes of cardiovascular system under simulated weightlessness. They were divided into control (5 men), hypoxia training (5 men) and Fangsong training (5 men) groups. 24 h dynamic ECG were recorded on the 2nd day of pre-bedrest, on the 3rd, 14th and 18th day of bedrest and on the 7th day of the post- bedrest. All spectra were estimated from entire 24 h HRV, before, during and after Fangsong and hypoxia training by autoregressive (AR) modeling method. Normalized low-frequency (LF%) was a quantitative marker of cardiac sympathetic activity, normalized high-frequency (HF%) reflected the changes in cardiac vagal activity, and LF/HF was considered to be related to sympathovagal balance or sympathetic activity. Result. In control group, LF% and HF% were all significantly reduced (P<0.05), LF/HL showed no significant changed during bedrest. In Fangsong group, HF% increased markedly (P< 0.05), while in hypoxia group, LF% increased markedly (P< 0.05). Conclusion. Fangsong training counteracted markedly the reduction in vagal activity, while hypoxia training counteracted markedly the decrease in sympathetic activity. It was possible that HRV indices could be used to evaluate the efficiency of countermeasures counteracting the adverse effects of weightlessness.

Effects of four herbal extracts on adjuvant-induced inflammation and hyperalgesia in rats.

OBJECTIVE: To evaluate the effects of four herbal medicine extracts on a rat model of inflammatory hyperalgesia. DESIGN/INTERVENTIONS: Inflammation was induced by injecting complete Freund's adjuvant (CFA) into one hindpaw of each rat. Four herbs that are routinely prescribed in Traditional Chinese Medicine for treatment of pain were used: Duhuo (Radix Angelicae Pubescentis), Bai jiang cao (Patriniae Herba cum Radice), Yan hu suo (Rhizoma Corydalis) and Sanqui (Panax Notoginseng). The crude water extracts of the herbs were inected intraperitoneally following a repeated treatment profile. OUTCOME MEASURES: Thermal hyperalgesia was assessed by testing each rat's paw withdrawal response to a noxious thermal stimulus. The magnitude of edema was determined by measuring the maximal thickness of the paw with a caliper. The effect of herb extracts on motor performance was assessed by using an accelerating rotarod test. RESULT: Duhuo, Bai jiang cao, and Yan hu suo significantly attenuated CFA-induced hyperalgesia at 2 hours and facilitated the recovery from hyperalgesia (p < 0.05), when compared to saline-treated rats. The CFA-induced edema was reduced by Duhuo at 24 hours, 72 hours and 168 hours; Bai jiang cao at 24 hours, and Yan hu suo at 24 hours and 168 hours. Sanqi did not produce any significant effect on inflammation and hyperalgesia. The rotarod performance was slightly reduced by Bai jiang cao, Yan hu suo, and Sanqi (p < 0.05) but not by Duhuo treatment. CONCLUSION: The present study identified Duhuo as a selective and effective herbal agent in attenuating persistent hindpaw inflammation and hyperalgesia in rats. These results indicate that some herbal agents may provide an alternative approach to the treatment of persistant inflammatory pain and hyperalgesia.

A clinical trial of tang shen ning for treatment of diabetic nephropathy.

This paper reports the clinical trial of Tang Shen Ning ([symbol: see text], TSN) for treating diabetic nephropathy (incipient and clinical, as divided by Mogensen). The results showed that the total effective rate in treatment group (TSN + western medicine) was 90.0%, and that in the control group (simply with western medicine), 56.7%. TSN plays important roles in decreasing proteinuria and improving renal functions.

Suckling and sucrose ingestion suppress persistent hyperalgesia and spinal Fos expression after forepaw inflammation in infant rats.

Sweet taste and nonnutritive suckling produce analgesia to transient noxious stimuli in infant rats and humans. The present study evaluated the pain-modulating effects of sucrose and suckling in a rat model of persistent pain and hyperalgesia that mimics the response to tissue injury in humans. Fore- and hindpaw withdrawal latencies from a 30 degrees or 48 degrees C brass stylus were determined in 10-day-old rats following paw inflammation induced by complete Freund's adjuvant (CFA; 1:1 injected s.c. in a 0.01 ml volume). CFA markedly decreased escape latencies to both 48 degrees and 30 degrees C stimulation, thereby demonstrating thermal hyperalgesia and mechanical allodynia. The combination of nonnutritive suckling and sucrose (7.5%, 0.01-0.06 ml/min) infusion markedly increased escape latencies to forepaw stimulation in both CFA-treated and control rats. In contrast, intraoral sucrose and suckling did not increase hindpaw withdrawal latencies in either control or CFA-inflamed rats. The effect was specific to sweet taste because neither water nor isotonic saline infusion affected forepaw escape latencies. Parallel findings were obtained for CFA-induced Fos-like immunoreactivity (Fos-LI), a marker of neuronal activation. Fos-LI was selectively induced in cervical and lumbar regions ipsilateral to forepaw and hindpaw inflammation, respectively. Suckling-sucrose treatment significantly reduced Fos-LI at the cervical but not at the lumbar regions. These findings demonstrate: (i) the development of persistent pain and hyperalgesia in 10-day-old rats that can be attenuated by endogenous pain-modulating systems activated by taste and nonnutritive suckling; (ii) the mediation of the sucrose-suckling analgesia and antihyperalgesia at the spinal level; and (iii) a differential rostrocaudal maturation of descending pain-modulating systems to the spinal cord of 10-day-old rats. These findings may provide new clinical approaches for engaging endogenous analgesic mechanisms in infants following tissue injury and inflammation.

A comparative study of the calcium-binding proteins calbindin-D28K, calretinin, calmodulin and parvalbumin in the rat spinal cord.

Comparison of the immunocytochemical localizations revealed distinct patterns of differential distribution and overlapping of calbindin-D28K (CB-D28K), calretinin (CR), calmodulin (CM) and parvalbumin (PV) in the rat spinal cord. In some areas, one of the four calcium-binding proteins (CBPs) appears to be predominant, for example, CB-D28K in lamina I and ependymal cells, PV at the inner part of laminae II, CR in laminae V and VI and CM in motoneurons of lamina IX. In other regions of the spinal cord, more than one CBPs was abundant. CB-D28K and CR were similarly distributed in lamina II and the lateral spinal and cervical nucleus; CM and PV were similarly abundant in the ventromedial dorsal horn, internal basilar and central cervical nucleus; CR and PV were similarly abundant in the ventromedial dorsal horn, internal basilar and central cervical nucleus; CR and PV were similarly heterogeneous in the gracile fasciculus from caudal to rostral spinal cord. In the sacral dorsal gray commissure, the distribution patterns of CR and PV were clearly complementary. The unilateral ganglionectomies resulted in a substantial reduction of CBP-like immunoreactivity (CBP-LI) in the dorsal columns and a reduction of CM- and PV-LI in the ventromedial dorsal horn. In the motor system, only CM labeled large motoneurons in lamina IX and CB-D28K lightly stained pyramidal tract. The apparent absence of CM-LI in the superficial dorsal horn is contradictory to the presence of a CM-dependent nitric oxide synthase in the region. These data indicate that most CBP-LI in the dorsal column pathway had primary afferent origin, while the superficial dorsal horn exhibited intrinsic CBP immunoreactivity. The differential and selective localizations of CBPs in the spinal cord suggest a role for these proteins in spinal nociceptive processing, visceral regulation and dorsal column sensory pathways.

Effects of electrical stimulation of vagal afferents on spinothalamic tract cells in the rat.

The effects of electrical stimulation of cervical vagal afferents (VAS) on the background activity and on the responses of 25 spinothalamic tract (STT) neurons to noxious stimuli were studied in anesthetized rats. Background (spontaneous) activity of 9 (36%) STT neurons was inhibited by all intensities of VAS. 6 (24%) units were facilitated at lesser and inhibited at greater intensities of VAS, 5 (20%) units were only facilitated by all intensities of VAS, and 5 (20%) units were not affected by VAS. Responses of 8 (36%) STT neurons to noxious stimuli were only inhibited by VAS, 9 (41%) were facilitated at lesser and inhibited at greater intensities of VAS, and 5 units (23%) were only facilitated by VAS. There were no significant differences in VAS-produced modulatory effects between STT neurons and 16 unidentified lumbar spinal dorsal horn neurons studied under the same conditions. These results reveal that descending facilitatory and inhibitory pathways engaged by activation of vagal afferents modulate rostrally projecting nociceptive transmission neurons in the spinal cord, constituting an important regulatory network for nociception.