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Acupuncture has been used to treat a variety of illness and involves the insertion and manipulation of needles into specific points on the body (termed “acupoints”). It has been suggested that acupoints are not merely discrete, static points, but can be dynamically changed according to the pathological state of internal organs. We investigated in a rat model of mustard oil (MO)-induced visceral hyperalgesia whether the number and size of acupoints were modified according to the severity of the colonic pain, and whether the changes were associated with enhanced activity of the spinal dorsal horn. In MO-treated rats, acupoints showing neurogenic inflammation (termed “neurogenic spots” or Neuro-Sps) were found both bilaterally and unilaterally on the leg. The number and size of these acupoints increased along with increasing doses of MO. Electroacupuncture of the acupoints generated analgesic effects on MO-induced visceral hypersensitivity. The MO-treated rats showed an increase in c-Fos expression in spinal dorsal horn neurons and displayed increased evoked activity and a prolonged after-discharge in spinal wide dynamic response (WDR) neurons in response to colorectal distension. Increased number and size of neurogenic inflammatory acupoints following MO treatment were reduced by inhibiting AMPA and NMDA receptors in the spinal cord. Our findings suggest that acupoints demonstrate increased number and size along with severity of visceral pain, which may be associated with enhanced neuronal responses in spinal dorsal horn neurons.

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.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with the hallmark characteristics of pruritus, psychological stress, and sleep disturbance, all possibly associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD). However, the etiology of the possible association between AD and ADHD is still not well understood. 2,4-dinitrochlorobenzene or corticosterone was used to evaluate the atopic symptom and its psychologic stress in the atopic mice model. Melatonin, corticotropin-releasing hormone, corticotropin-releasing hormone receptor, urocortin, proopiomelanocortin, adrenocorticotropic hormone, corticosterone, cAMP, cAMP response element-binding protein, dopamine and noradrenaline were analyzed spectrophotometrically, and the expression of dopamine beta-hydroxylase and tyrosine hydroxylase were measured by Western blotting or immunohistochemistry. AD-related psychological stress caused an increase in the levels of dopamine beta-hydroxylase and tyrosine hydroxylase, degradation of melatonin, hyper-activity of the hypothalamic-pituitary-adrenal axis, and dysregulation of dopamine and noradrenaline levels (ADHD phenomena) in the locus coeruleus, prefrontal cortex, and striatum of the AD mouse brain. Notably, melatonin administration inhibited the development of ADHD phenomena and their-related response in the mouse model. This study demonstrated that AD-related psychological stress increased catecholamine dysfunction and accelerated the development of psychiatric comorbidities, such as ADHD.

Methamphetamine (MA) is a highly addictive psychostimulant that disturbs the central nervous system; therefore, diagnosis of MA addiction is important in clinical and forensic toxicology. In this study, a MA self-administration rat model was used to illustrate the gene expression profiling of the rewarding effect caused by MA. RNA-sequencing was performed to examine changes in gene expression in rat whisker follicles collected before self-administration, after MA self-administration, and after withdrawal sessions. We identified six distinct groups of genes, with statistically significant expression patterns. By constructing the functional association network of these genes and performing the subsequent topological analysis, we identified 43 genes, which have the potential to regulate MA reward and addiction. The gene pathways were then analysed using the Reactome and Knowledgebase for Addiction-Related Gene database, and it was found that genes and pathways associated with Alzheimer’s disease and the heparan sulfate biosynthesis were enriched in MA self-administration rats. The findings suggest that changes of the genes identified in rat whisker follicles may be useful indicators of the rewarding effect of MA. Further studies are needed to provide a comprehensive understanding of MA addiction.

While our recent studies have suggested that effective acupoints display neurogenic inflammation and can be identified as neurogenic spots (Neuro-Sps), the optimal stimulation conditions and the underlying mechanisms remain uncharacterized. We developed a combined mechano-electrical acupuncture device (MEA) and examined the effects of acupuncture at Neuro-Sps on systolic blood pressure (BP) in a rat model of immobilization-induced hypertension (IMH) and the mediation of endogenous opioid systems in its effect. Cutaneous neurogenic spots were found mostly in the forelimb. Electrical and mechanical acupuncture of Neuro-Sps increased 22-kHz ultrasonic vocalizations (USVs), c-Fos expression and cell excitability in the midbrain and synergistically alleviated the development of hypertension following immobilization stress, which was prevented by administration of the opioid antagonist naloxone into the rostral ventrolateral medulla (rVLM). These findings suggest that mechanical and electrical stimulation at Neuro-Sps suppresses the development of hypertension via mediation of the endogenous opioid system.

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.

Acupuncture affects the central nervous system via the regulation of neurotransmitter transmission. We previously showed that Shemen (HT7) acupoint stimulation decreased cocaine-induced dopamine release in the nucleus accumbens. Here, we used the intracranial self-stimulation (ICSS) paradigm to evaluate whether HT stimulation regulates the brain reward function of rats. We found that HT stimulation triggered a rightward shift of the frequency–rate curve and elevated the ICSS thresholds. However, HT7 stimulation did not affect the threshold-lowering effects produced by cocaine. These results indicate that HT7 points only effectively regulates the ICSS thresholds of the medial forebrain bundle in drug-naïve rats.

Electrical skin measurements at acupuncture points (acupoints) have been utilized as a diagnostic and therapeutic aid for more than 50 years. Although acupoints are described as having distinct electrical properties, such as high conductance and low impedance, the underlying mechanisms are currently unknown. The present study investigated in a rat model of hypertension whether the high conductance at acupoints is a result of the release of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) during neurogenic inflammation in the referred pain area. When plasma extravasation from neurogenic inflammation was examined by exploring the leakage of intravenously injected Evans blue dye (EBD) to the skin, extravasated EBD was found most frequently in acupoints on the wrist. The increased conductance and temperature at these acupoints occurred during the development of hypertension. The increase in conductance and plasma extravasation at acupoints in hypertensive rats was ablated by cutting median and ulnar nerves, blocking small diameter afferent fibers with resiniferatoxin (RTX) injection into median and ulnar nerves, or antagonizing SP or CGRP receptors in acupoints. In turn, intradermal injection of SP or CGRP resulted in increased conductance and plasma extravasation in naïve rats. Elevated levels of SP and CGRP were found in the acupoints of hypertensive rats. These findings suggest that the high conductance at acupoints is due to vascular leakage following local release of SP and CGRP during neurogenic inflammation.

Dopamine (DA) is a cell signaling molecule that does not readily cross the blood brain barrier. Despite this, peripherally administered DA enhances DA levels in the nucleus accumbens and alters DA-related behaviors. This study was designed to investigate whether DA subtype-2 receptors are involved in the enhancement of nucleus accumbens (NAc) DA levels elicited by intravenous DA administration. This was accomplished by using microdialysis in the NAc and extracellular single unit recordings of putative DA neurons in the ventral tegmental area (VTA). Additionally, the reinforcing properties of intravenous DA were investigated using a place conditioning paradigm and the effects of intravenous DA on ultrasonic vocalizations were assessed. Following administration of intravenous dopamine, the firing rate of putative DA neurons in the VTA displayed a biphasic response and DA levels in the nucleus accumbens were enhanced. Pretreatment with domperidone, a peripheral-only DA D2 receptor (D2R) antagonist, reduced intravenous DA mediated increases in VTA DA neuron activity and NAc DA levels.. Pretreatment with phentolamine, a peripheral α-adrenergic receptor antagonist, did not alter the effects of IV DA on mesolimbic DA neurotransmission. These results provide evidence for peripheral D2R mediation of the effects of intravenous DA on mesolimbic DA signaling.

Background:Previous studies suggested that opiate withdrawal may increase anxiety and disrupt brain-derived neurotrophic factor function, but the effects of i.v. morphine self-administration on these measures remain unclear.Methods:Adult male Sprague-Dawley rats were implanted with a catheter in the jugular vein. After 1 week of recovery, the animals were allowed to self-administer either i.v. morphine (0.5 mg/kg per infusion, 4 h/d) or saline in the operant conditioning chambers. The acoustic startle reflex and prepulse inhibition were measured at a baseline and on self-administration days 1, 3, 5, and 7 (1- and 3-hour withdrawal). Blood samples were collected on self-administration days 3, 5, and 7 from separate cohorts of animals, and the levels of brain-derived neurotrophic factor and corticosterone were assayed using the enzyme-linked immunosorbent assay method.Results:Compared with the saline group, the morphine self-administration group showed hyper-locomotor activity and reduced defecation during the self-administration. The morphine self-administration increased acoustic startle reflex at 1-hour but not 3-hour withdrawal from morphine and disrupted prepulse inhibition at 3-hour but not 1-hour withdrawal. The blood brain-derived neurotrophic factor levels were decreased in the morphine self-administration group at self-administration days 3 and 5, while the corticosterone levels remained unchanged throughout the study.Conclusions:The current findings suggest that spontaneous withdrawal from i.v. morphine self-administration may have transient effects on acoustic startle, sensorimotor gating, and peripheral brain-derived neurotrophic factor levels, and these changes may contribute to the adverse effects of opiate withdrawal.