Excitatory GABAergic Action and Increased Vasopressin Synthesis in Hypothalamic Magnocellular Neurosecretory Cells Underlie the High Plasma Level of Vasopressin in Diabetic Rats.

Diabetes mellitus (DM) is associated with increased plasma levels of arginine-vasopressin (AVP), which may aggravate hyperglycemia and nephropathy. However, the mechanisms by which DM may cause the increased AVP levels are not known. Electrophysiological recordings in supraoptic nucleus (SON) slices from streptozotocin (STZ)-induced DM rats and vehicle-treated control rats revealed that γ-aminobutyric acid (GABA) functions generally as an excitatory neurotransmitter in the AVP neurons of STZ rats, whereas it usually evokes inhibitory responses in the cells of control animals. Furthermore, Western blotting analyses of Cl- transporters in the SON tissues indicated that Na+-K+-2Cl- cotransporter isotype 1 (a Cl- importer) was upregulated and K+-Cl- cotransporter isotype 2 (KCC2; a Cl- extruder) was downregulated in STZ rats. Treatment with CLP290 (a KCC2 activator) significantly lowered blood AVP and glucose levels in STZ rats. Last, investigation that used rats expressing an AVP-enhanced green fluorescent protein fusion gene showed that AVP synthesis in AVP neurons was much more intense in STZ rats than in control rats. We conclude that altered Cl- homeostasis that makes GABA excitatory and enhanced AVP synthesis are important changes in AVP neurons that would increase AVP secretion in DM. Our data suggest that Cl- transporters in AVP neurons are potential targets of antidiabetes treatments.

The effects of Chamaecyparis obtusa essential oil on pain-related behavior and expression of pro-inflammatory cytokines in carrageenan-induced arthritis in rats.

Chamaecyparis obtusa essential oil (COE) has been widely used to treat allergic diseases and was suggested to exert anti-inflammatory, antioxidant, and antimicrobial effects. This study evaluated the effects of COE on pain-related behavior and pro-inflammatory cytokines in rats with carrageenan (CGN)-induced arthritis. Reduced dynamic weight load on inflamed joint in voluntarily walking rats was used as the behavior test for arthritic pain; 10% COE-treated group was significantly attenuated pain (6-8 h post-CGN injection) compared to VEH (mineral oil)-treated group. In addition, the protein levels of interleukin (IL)-1ß, tumor necrosis factor-α, IL-6 (6-8 h), and cyclooxygenase (COX)-2 (8 h) within the synovial membrane, as well as IL-1ß, COX-2 (6-8 h), and IL-6 (5-7 h) within the meniscus, of 10% COE-treated group were significantly reduced. The current results implicate that COE has anti-inflammatory and anti-nociceptive effects on arthritis in rats.

Immediate therapeutic effect of interferential current therapy on spasticity, balance, and gait function in chronic stroke patients: a randomized control trial.

OBJECTIVE: To determine whether a single trial of interferential current therapy (ICT) can immediately alleviate spasticity and improve balance and gait performance in patients with chronic stroke. DESIGN: Randomized, placebo-controlled clinical trial. SETTING: Inpatient rehabilitation in a local center. SUBJECTS: A total of 42 adult patients with chronic stroke with plantar flexor spasticity of the lower limb. INTERVENTION: The ICT group received a single 60-minute ICT stimulation of the gastrocnemius in conjunction with air-pump massage. In the placebo-ICT group, electrodes were placed and air-pump massage performed without electrical stimulation. MAIN MEASURES: After a single ICT application, spasticity was measured immediately using the Modified Ashworth Scale (MAS), and balance and functional gait performance were assessed using the following clinical tools: Functional Reach Test (FRT), Berg Balance Scale (BBS), Timed Up and Go Test (TUG), and 10-m Walk Test (10MWT). RESULTS: Gastrocnemius spasticity significantly decreased in the ICT group than in the placebo-ICT group (MAS: ICT vs placebo-ICT: 1.55±0.76 vs 0.40±0.50). The ICT group showed significantly greater improvement in balance and gait abilities than the placebo-ICT group (FRT: 2.62±1.21 vs 0.61±1.34, BBS: 1.75±1.52 vs 0.40±0.88, TUG: 6.07±6.11 vs 1.68±2.39, 10MWT: 7.02±7.02 vs 1.96±3.13). Spasticity correlated significantly with balance and gait abilities (P < 0.05). CONCLUSION: A single trial of ICT is a useful intervention for immediately improving spasticity, balance, and gait abilities in chronic stroke patients, but not for long-term effects. Further study on the effects of repeated ICT is needed.

A single trial of transcutaneous electrical nerve stimulation reduces chronic neuropathic pain following median nerve injury in rats.

Neuropathic pain is a devastating chronic condition and is often induced in the upper limb following nerve injury or damage. Various drugs or surgical methods have been used to manage neuropathic pain; however, these are frequently accompanied by undesirable side effects. Transcutaneous electrical nerve stimulation (TENS) is a safe and non-invasive intervention that has been used to alleviate different types of pain in the clinic, but it is unclear whether TENS can improve chronic neuropathic pain in the upper limb. Thus, the aim of this study was to investigate the effects of a single trial of TENS on chronic neuropathic pain following median nerve injury. Male rats weighing 200-250 g received median nerve-ligation of the right forearm, while the control group received only skin-incision without nerve-ligation. Neuropathic pain-behaviors, including mechanical, cold, and thermal allodynia, were measured for 4 weeks. After the development of chronic neuropathic pain, TENS (100 Hz, 200 µs, sub-motor threshold) or placebo-TENS (sham stimulation) was applied for 20 min to the ipsilateral or contralateral side. Neuropathic pain behavior was assessed before and after intervention. Median nerve-ligation significantly induced and maintained neuropathic pain in the ipsilateral side. TENS application to the ipsilateral side effectively attenuated the three forms of chronic neuropathic pain in the ipsilateral side compared to sham-treated rats (peripheral and central effects), while TENS application to contralateral side only reduced mechanical allodynia in the ipsilateral side (central effect). Our findings demonstrate that TENS can alleviate chronic neuropathic pain following median nerve injury.

GABAergic excitation of vasopressin neurons: possible mechanism underlying sodium-dependent hypertension.

RATIONALE: Increased arginine-vasopressin (AVP) secretion is a key physiological response to hyperosmotic stress and may be part of the mechanism by which high-salt diets induce or exacerbate hypertension. OBJECTIVE: Using deoxycorticosterone acetate-salt hypertension model rats, we sought to test the hypothesis that changes in GABA(A) receptor-mediated inhibition in AVP-secreting magnocellular neurons contribute to the generation of Na(+)-dependent hypertension. METHODS AND RESULTS: In vitro gramicidin-perforated recordings in the paraventricular and supraoptic nuclei revealed that the GABAergic inhibition in AVP-secreting neurons was converted into excitation in this model, because of the depolarization of GABA equilibrium potential. Meanwhile, in vivo extracellular recordings in the supraoptic nuclei showed that the GABAergic baroreflexive inhibition of magnocellular neurons was transformed to excitation, so that baroreceptor activation may increase AVP release. The depolarizing GABA equilibrium potential shift in AVP-secreting neurons occurred progressively over weeks of deoxycorticosterone acetate-salt treatment along with gradual increases in plasma AVP and blood pressure. Furthermore, the shift was associated with changes in chloride transporter expression and partially reversed by bumetanide (Na(+)-K(+)-2Cl(-) cotransporter inhibitor). Intracerebroventricular bumetanide administration during deoxycorticosterone acetate-salt treatment hindered the development of hypertension and rise in plasma AVP level. Muscimol (GABA(A) agonist) microinjection into the supraoptic nuclei in hypertensive rats increased blood pressure, which was prevented by previous intravenous V1a AVP antagonist injection. CONCLUSIONS: We conclude that the inhibitory-to-excitatory switch of GABAA receptor-mediated transmission in AVP neurons contributes to the generation of Na(+)-dependent hypertension by increasing AVP release. We speculate that normalizing the GABA equilibrium potential may have some utility in treating Na(+)-dependent hypertension.

Chronic hyperosmotic stress converts GABAergic inhibition into excitation in vasopressin and oxytocin neurons in the rat.

In mammals, the increased secretion of arginine-vasopressin (AVP) (antidiuretic hormone) and oxytocin (natriuretic hormone) is a key physiological response to hyperosmotic stress. In this study, we examined whether chronic hyperosmotic stress weakens GABA(A) receptor-mediated synaptic inhibition in rat hypothalamic magnocellular neurosecretory cells (MNCs) secreting these hormones. Gramicidin-perforated recordings of MNCs in acute hypothalamic slices prepared from control rats and ones subjected to the chronic hyperosmotic stress revealed that this challenge not only attenuated the GABAergic inhibition but actually converted it into excitation. The hyperosmotic stress caused a profound depolarizing shift in the reversal potential of GABAergic response (E(GABA)) in MNCs. This E(GABA) shift was associated with increased expression of Na(+)-K(+)-2Cl(-) cotransporter 1 (NKCC1) in MNCs and was blocked by the NKCC inhibitor bumetanide as well as by decreasing NKCC activity through a reduction of extracellular sodium. Blocking central oxytocin receptors during the hyperosmotic stress prevented the switch to GABAergic excitation. Finally, intravenous injection of the GABA(A) receptor antagonist bicuculline lowered the plasma levels of AVP and oxytocin in rats under the chronic hyperosmotic stress. We conclude that the GABAergic responses of MNCs switch between inhibition and excitation in response to physiological needs through the regulation of transmembrane Cl(-) gradients.

Pain-relieving effects of acupuncture and electroacupuncture in an animal model of arthritic pain.

The effects of acupuncture and electroacupuncture on an animal model of arthritic pain were examined. Under halothane anesthesia, arthritic pain was induced by the injection of carrageenan into the knee joint cavity of male Sprague-Dawley rats. Behavioral performance was tested before and after the termination of acupuncture or electroacupuncture. Electrophysiologically, the responses of afferents to a movement cycle were recorded before and after acupuncture or electroacupuncture. After the acupuncture procedure, the weight-bearing force of the rats was significantly improved and the neural responses to noxious movement stimulation were reduced. Electroacupuncture significantly improved weight-bearing behavior and inhibited neural responses of articular afferents to noxious stimulation. These results indicate that acupuncture and electroacupuncture may provide a potent strategy in relieving arthritic pain.

Heart rate variability and obesity indices: emphasis on the response to noise and standing.

BACKGROUND: Obese people have a higher prevalence of cardiovascular disease, but the mechanism of this result remains obscure. The purpose of this study was to prove heart rate variability (HRV) response at rest and during stimuli in these persons. METHODS: The subjects were 41 healthy persons (19 men, 22 women) ranging in age from 20 to 65 years. HRV was measured at rest and at given stresses with noise and standing. RESULTS: Higher levels of fat mass, percentage fat content, and waist/hip ratio were significantly associated with lower low frequency (LF) (r = -0.34, r = -0.43; P < .01, r = -0.33, P < .05), and lower root mean square differences of successive NN intervals (RMS standard deviation) (r = -0.33, r = -0.35, r = -0.38, P < .05). During rest, noise, and standing, the change amount of the standard deviation of NN interval (SDNN) and low frequency/high frequency ratio were not different between normal and obese groups (P > .05). CONCLUSION: Although there was no significant HRV response to stimuli, root mean square of successive differences (which reflects parasympathetic acivity) and low frequency (which mainly reflects sympathetic activity) were negatively correlated with fat mass, fat percentage, and waist-to-hip ratio at rest in obese persons. These results mean obesity can change cardiac autonomic nervous response, meaning that the mechanism by which obesity increases cardiac mortality would be explained, at least partially.

Local neurokinin-1 receptor in the knee joint contributes to the induction, but not maintenance, of arthritic pain in the rat.

Substance P is known to exert various pro-inflammatory effects that are mediated by neurokinin-1 (NK-1) receptor in peripheral tissues. This study examined the effect of the NK-1 receptor antagonist cis-2-[diphenylmethyl]-N-[(2-iodophenyl)-1-azabicyclo[2.2.2]octan-3-amine] (L-703,606) on nociceptive response following carrageenan injection (2%, 50 microl) into the knee joint cavity of the right hind leg. L-703,606 injection (0.1 or 1 mM, 50 microl) into the same joint cavity immediately before the carrageenan injection significantly reduced the nociceptive response. However, antagonist treatment at 5 h after carrageenan injection was ineffective in alleviating nociception. Neither intraperitoneal injection of the antagonist (1 mM, 50 microl) immediately before the carrageenan injection was effective. These results suggest that local NK-1 receptor contributes to the induction, but not maintenance, of arthritic pain.