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Neuronal hyperexcitability produces enhanced pain transmission in the spinal dorsal horn after spinal cord injury (SCI). Spontaneous and evoked neuronal excitability normally are well controlled by neural circuits. However, SCI produces maladaptive synaptic circuits in the spinal dorsal horn that result in neuronal hyperexcitability. After SCI, activated primary afferent neurons produce enhanced release of glutamate, neuropeptides, adenosine triphosphate, and proinflammatory cytokines, which are known to be major components for pain transmission in the spinal dorsal horn. Enhanced neurochemical events contribute to neuronal hyperexcitability, and neuroanatomical changes also contribute to maladaptive synaptic circuits and neuronal hyperexcitability. These neurochemical and neuroanatomical changes produce enhanced cellular signaling cascades that ensure persistently enhanced pain transmission. This review describes altered neurochemical and neuroanatomical contributions on neuronal hyperexcitability in the spinal dorsal horn, which serve as substrates for central neuropathic pain after SCI.

Previous studies have demonstrated that somatosensory stimuli influence dopamine transmission in the mesolimbic reward system and can reduce drug-induced motor behaviors, craving and dependence. Until now, the central links between somatosensory and brain reward systems are not known. Here, we show that the dorsal column (DC) somatosensory pathway contains projections that convey an inhibitory input from the periphery to mesolimbic reward circuits. Stimulation of the ulnar nerve under HT7 acupoint suppressed psychomotor response to cocaine, which was abolished by disruption of the DC pathway, but not the spinothalamic tract (STT). Low-threshold or wide-dynamic range neurons in the cuneate nucleus (CN) were excited by peripheral stimulation. Lesions of dorsal column or lateral habenula (LHb) prevented the inhibitory effects of peripheral stimulation on cocaine-induced neuronal activation in the nucleus accumbens (NAc). LHb neurons projecting to the ventral tegmental area (VTA)/rostromedial tegmental nucleus (RMTg) regions were activated by peripheral stimulation and LHb lesions reversed the inhibitory effects on cocaine locomotion produced by peripheral stimulation. These findings suggest that there exists a pathway in spinal cord that ascends from periphery to mesolimbic reward circuits (spino-mesolimbic pathway) and the activation of somatosensory input transmitted via the DC pathway can inhibit the psychomotor response to cocaine.

In this study, we investigated the role of the spinal GABAergic system in central neuropathic painlike outcomes following spinal cord injury (SCI) produced by a spinal hemitransection at T13 of the rat. After SCI, mechanical allodynia develops bilaterally in both hind paws of the rat, lasting longer than 40 days, as evidenced by an increase in paw withdrawal frequency in response to a weak von Frey filament. In naive rats, intrathecal (i.t.) administration in the lumbar spinal cord of GABAA and GABAB receptor antagonists, bicuculline (1–5 µg) and phaclofen (0.1–5 µg), respectively, causes a dose-dependent increase in the magnitude of mechanical allodynia. The SCI-induced mechanical allodynia in both hind-paws is attenuated by i.t. administration in the lumbar spinal cord of GABAA or GABAB receptor agonists, muscimol (1 µg) or baclofen (0.5 µg), respectively. In electrophysiological experiments, rats with SCI show a bilateral increase in hyperexcitability in response to natural stimuli in wide dynamic range (WDR) neurons in the lumbar spinal dorsal horn. The topical application of muscimol (1 µg) or baclofen (0.5 µg) onto the lumbar cord surface reduce the SCIinduced increased responsiveness of WDR neurons. Inhibitory effects of muscimol and baclofen on both the behavioral mechanical allodynia and the hyperexcitability in WDR neuron with SCI compared to controls, were antagonized by pre-treatment of bicuculline (10 µg) and phaclofen (5 µg), respectively. This study provides behavioral and electrophysiological evidence for the important role of the loss of spinal inhibitory tone, mediated by activation of both GABAA and GABAB receptors, in the development of central neuropathic pain following SCI.

Spinal cord injury (SCI) often leads to chronic central pain (CCP) syndromes such as allodynia and hyperalgesia. Although several experimental animal models for CCP studies exist, little is known about the effect of age on the development of CCP following SCI. In this study, we evaluated behavioral responses to mechanical and thermal stimuli following SCI using three different age groups of adult Sprague-Dawley rats: young (40 days), adult (60 days), and middle-age (12 months). SCI was produced by unilateral hemisection of the spinal cord at T13. Behavioral measures of locomotor function were assayed in open field tests and somatosensory function by paw withdrawal frequency (PWF) to innocuous mechanical stimuli and paw withdrawal latency (PWL) to radiant heat stimuli on both the forelimbs and hindlimbs. Prior to hemisection, the PWF was not different between the three groups; however, the PWL of the young group was significantly greater than the adult and middle-age group. After spinal hemisection, spontaneous locomotor recovery occurred more rapidly in young and adult than in middle-age rats. In both forelimbs and hindlimbs, the young group displayed a significant increase in PWF and a significant decrease in PWL compared to presurgical and sham values or values from the adult and middle-age groups. These results indicate that younger rats developed more robust neuropathic behaviors than middle-age rats, indicating that age selection is an important factor in animal models of CCP syndromes following SCI. Additionally, our data suggest that age at the time of injury may be one risk factor in predicting the development of CCP after SCI in people.

Acupuncture, a traditional medical procedure practised for over 2000 years in Asia, stimulates specific but poorly defined sites called acupoints. To date, no unique anatomical acupoint structures have been found. However, noxious sensory signals from visceral organs produce hypersensitive spots on the skin (neurogenic spots), caused by cutaneous neurogenic inflammation, in the dermatome that overlaps with visceral afferent innervations. Here, we show that an acupoint is one form of neurogenic inflammation on the skin. Various studies have demonstrated that acupoints show mechanical hypersensitivity and have high electrical conductance. Stimulation of acupoints produces needling sensations caused by the activation of small diameter afferent nerve fibres and therapeutic effects on the associated visceral organs, which is likely due to the release of endogenous opioids. The present study provides experimental evidence that neurogenic spots exhibit all the characteristics of the acupoints listed above. In addition, the stimulation of neurogenic spots by electrical, mechanical, or chemical means alleviated pathological conditions in rat colitis and hypertension models via the endogenous opioid system. Our results suggest that acupoints associated with internal organs may be identical to neurogenic inflammatory spots on the skin, which are produced by activation of somatic afferents in abnormal conditions of visceral organs.

High blood pressure (BP) is a highly controllable risk factor for cardiovascular diseases; however, awareness of this condition and the rates of controlled hypertension are low. Experimental animal studies have shown that stimulation of the median nerve or PC6 acupoint over the wrist has effects on cardiovascular activities, including reductions in systolic and diastolic BPs. A proof-of-concept study was conducted in humans to investigate whether stimulation of median nerve near PC6 acupoint decreased high BP, identify the optimal stimulation parameters for the BP-lowering effects of median nerve stimulation, and determine the specific peripheral nerves or types of afferent fibers mediating the BP-lowering effects. Median nerve stimulation was carried out bilaterally or unilaterally with different stimulation parameters, and the BP and heart rate were monitored. The afferent mechanisms underlying the effects of median nerve stimulation on hypertension were investigated via microneurography, A-fiber blocking experiments, and localized chemical or electrical stimulation. Bilateral median nerve stimulation at either low or high frequencies produced profound but transient reductions in systolic BP, which were elicited when median nerve stimulation was unilaterally applied at interelectrode distances of 2 and 4 cm. Systolic BP was also reduced by electrical stimulation of the thumb on the palm side. Although microneurographic recordings revealed the excitation of both A- and C-fibers following median nerve stimulation, the median nerve-mediated reductions in BP were not affected by A-fiber blockade, and they were mimicked by the activation of C-fibers with capsaicin. The present results indicate that activation of C-fibers in the median nerve generates BP-lowering effects in humans. Based on our clinical study, an optimized median nerve stimulator was built and combined with a wrist BP monitor for simultaneous BP measurements and median nerve stimulation.

In the present study, we compared the roles of gracile neurons in mechanically-induced neuropathic pain caused by spinal injury and L5 spinal nerve ligation in rats. Behavioral and electrophysiological methods were used to measure mechanical allodynia in the hindpaws, and excitability of the gracile neurons in the medulla, respectively. In the spinal hemisection and spinal contusion models, mechanical allodynia developed in both hindpaws and lasted over a month. Three weeks following the hemisection, gracile neurons identified as wide-dynamic-range (WDR) and low-threshold (LT) neurons, showed increased neuronal activity to non-noxious mechanical stimuli compared to control groups, whereas the spinal contusion groups did not show evoked activity (*p<0.05). A lesion of the gracile nucleus partially reversed the existing mechanical allodynia in both hindpaws compared to prior to the injury in the hemisection group, whereas the spinal contusion groups did not show significant changes (*p<0.05). In the spinal nerve ligation model, mechanical allodynia developed at the ipsilateral (injured) side of the hindpaw. In addition, WDR neuronal activity at the ipsilateral gracile neurons showed a significant increase with non-noxious mechanical stimuli, whereas the LT neurons did not show significant changes (*p<0.05). Similarly to the hemisection model, a lesion of the gracile nucleus attenuated the mechanical allodynia in spinal nerve ligation models. The present data suggest that gracile neurons contribute to the maintenance of non-noxious mechanically-induced neuropathic pain in both hemisection- and ligation-induced neuropathic pain in rats.

In this study, the antibacterial activity of essential oil from Chamaecyparis obtusa (Sieb. et Zucc) leaves and twigs was investigated. The test strains were Klebsiella pneumoniae, Listeria monocytogenes, Salmonella typhimurium, Staphylococcus aureus, Escherichia coli, Legionella pneumophila, and Methicilline-resistant Staphylococcus aureus. Antibacterial activity was estimated by measuring bacterial growth inhibition. Histopathological examination was also performed. C. obtusa oil distinctly inhibited the growth of all test strains and exhibited the strongest antibacterial activity against L. monocytogenes. It was chromatographically divided into several fractions. The fractions were further tested against antibacterial activity and their chemical compositions were analyzed. The fraction containing terpinen-4-ol (TA) showed high antibacterial activity toward all strains tested. Tests with authentic samples showed that TA played a major role in the antibacterial activity of C. obtusa oil, and in a mice test, the oil actively minimized inflammation by S. aureus.

The sap of Acer mono has been called ‘bone-benefit-water’ in Korea because of its mineral and sugar content. In particular, the calcium concentration of the sap of A. mono is 37·5 times higher than commercial spring water. In the current study, we examined whether A. mono sap could improve or prevent osteoporosis-like symptoms in a mouse model. Male mice (3 weeks old) were fed a low-calcium diet supplemented with 25, 50 or 100 % A. mono sap, commercial spring water or a high calcium-containing solution as a beverage for 7 weeks. There were no differences in weekly weight gain and food intake among all the groups. Mice that were given a low-calcium diet supplemented with commercial spring water developed osteoporosis-like symptoms. To assess the effect of sap on osteoporosis-like symptoms, we examined serum calcium concentration, and femur density and length, and carried out a histological examination. Serum calcium levels were significantly lower in mice that received a low-calcium diet supplemented with commercial spring water (the negative control group), and in the 25 % sap group compared to mice fed a normal diet, but were normal in the 50 and 100 % sap and high-calcium solution groups. Femur density and length were significantly reduced in the negative control and 25 % sap groups. These results indicate that a 50 % sap solution can mitigate osteoporosis-like symptoms induced by a low-calcium diet. We also examined the regulation of expression of calcium-processing genes in the duodenum and kidney. Duodenal TRPV6 and renal calbindin-D9k were up-regulated dose-dependently by sap, and the levels of these factors were higher than those attained in the spring water-treated control. The results demonstrate that the sap of A. mono ameliorates the low bone density induced by a low-calcium diet, most likely by increasing calcium ion absorption.