In recent years, growing evidence indicates that the nervous system plays an indispensable role in tumor development and metastasis. Elucidating crosstalk between the nervous system and tumor progression has thrived as a hot topic and a new direction for understanding cancer pathogenesis. Notably, many novel discoveries have suggested that neurotransmitter receptors (NRs) are not only widely expressed in cancer cells, but also play key roles in regulating cancer initiation and progression by diverse approaches. In this review, we summarized the latest advance in cancer neuroscience, especially emphasizing the important roles of different NRs in cancer development and prevention. The exemplary studies presented herein illustrate the emerging view that NRs are profoundly influential, manifested in tumor growth, apoptosis, angiogenesis, metastasis, resistance to drugs, and participate in the formation of neural-cancer interactions. In addition, NRs also regulate cellular metabolic processes and tumor microenvironment (TME) remodeling. More importantly, numerous basic and clinical studies have suggested that NRs may be potential targets for cancer treatments, and corresponding agonists or antagonists have been identified effectively in controlling tumor growth and metastasis. In conclusion, NRs are emerging as novel targets for anti-cancer drug exploration and clinical cancer treatments, while trying to uncover deeper mechanisms and connections between NRs and cancer is of high clinical significance and translational value.
Humans ; Neoplasms/metabolism* ; Receptors, Neurotransmitter/physiology* ; Animals ; Tumor Microenvironment/physiology*

Neuropathic pain is a chronic debilitating symptom characterized by spontaneous pain and mechanical allodynia. It occurs in distinct forms, including brush-evoked dynamic and filament-evoked punctate mechanical allodynia. Potassium channel 2.1 (Kir2.1), which exhibits strong inward rectification, is and regulates the activity of lamina I projection neurons. However, the relationship between Kir2.1 channels and mechanical allodynia is still unclear. In this study, we first found that pretreatment with ML133, a selective Kir2.1 inhibitor, by intrathecal administration, preferentially inhibited dynamic, but not punctate, allodynia in mice with spared nerve injury (SNI). Intrathecal injection of low doses of strychnine, a glycine receptor inhibitor, selectively induced dynamic, but not punctate allodynia, not only in naïve but also in ML133-pretreated mice. In contrast, bicuculline, a GABA receptor antagonist, induced only punctate, but not dynamic, allodynia. These results indicated the involvement of glycinergic transmission in the development of dynamic allodynia. We further found that SNI significantly suppressed the frequency, but not the amplitude, of the glycinergic spontaneous inhibitory postsynaptic currents (gly-sIPSCs) in neurons on the lamina II-III border of the spinal dorsal horn, and pretreatment with ML133 prevented the SNI-induced gly-sIPSC reduction. Furthermore, 5 days after SNI, ML133, either by intrathecal administration or acute bath perfusion, and strychnine sensitively reversed the SNI-induced dynamic, but not punctate, allodynia and the gly-sIPSC reduction in lamina IIi neurons, respectively. In conclusion, our results suggest that blockade of Kir2.1 channels in the spinal dorsal horn selectively inhibits dynamic, but not punctate, mechanical allodynia by enhancing glycinergic inhibitory transmission.
Animals ; Bicuculline ; pharmacology ; Disease Models, Animal ; Glycine ; metabolism ; Hyperalgesia ; drug therapy ; etiology ; metabolism ; Imidazoles ; pharmacology ; Inhibitory Postsynaptic Potentials ; drug effects ; physiology ; Male ; Mice, Inbred C57BL ; Neurons ; drug effects ; metabolism ; Neurotransmitter Agents ; pharmacology ; Peripheral Nerve Injuries ; drug therapy ; metabolism ; Phenanthrolines ; pharmacology ; Potassium Channels, Inwardly Rectifying ; antagonists & inhibitors ; metabolism ; Receptors, GABA-A ; metabolism ; Receptors, Glycine ; metabolism ; Strychnine ; pharmacology ; Synaptic Transmission ; drug effects ; physiology ; Tissue Culture Techniques ; Touch

The autonomic nervous system plays critical roles in maintaining homeostasis in humans, directly regulating inflammation by altering the activity of the immune system. The cholinergic anti-inflammatory pathway is a well-studied neuroimmune interaction involving the vagus nerve. CD4-positive T cells expressing β2 adrenergic receptors and macrophages expressing the alpha 7 subunit of the nicotinic acetylcholine receptor in the spleen receive neurotransmitters such as norepinephrine and acetylcholine and are key mediators of the cholinergic anti-inflammatory pathway. Recent studies have demonstrated that vagus nerve stimulation, ultrasound, and restraint stress elicit protective effects against renal ischemia-reperfusion injury. These protective effects are induced primarily via activation of the cholinergic anti-inflammatory pathway. In addition to these immunological roles, nervous systems are directly related to homeostasis of renal physiology. Whole-kidney three-dimensional visualization using the tissue clearing technique CUBIC (clear, unobstructed brain/body imaging cocktails and computational analysis) has illustrated that renal sympathetic nerves are primarily distributed around arteries in the kidneys and denervated after ischemia-reperfusion injury. In contrast, artificial renal sympathetic denervation has a protective effect against kidney disease progression in murine models. Further studies are needed to elucidate how neural networks are involved in progression of kidney disease.
Acetylcholine ; Arteries ; Autonomic Nervous System ; Cholinergic Neurons ; Homeostasis ; Humans ; Immune System ; Inflammation ; Kidney Diseases ; Kidney ; Macrophages ; Nervous System ; Neurotransmitter Agents ; Norepinephrine ; Optogenetics ; Physiology ; Receptors, Adrenergic ; Receptors, Nicotinic ; Reperfusion Injury ; Spleen ; Sympathectomy ; Sympathetic Nervous System ; T-Lymphocytes ; Ultrasonography ; Vagus Nerve ; Vagus Nerve Stimulation

BACKGROUND/AIMS: Urocortin 1, a corticotropin-releasing factor related peptide, increases colonic motility under stressful conditions. We investigated the effect of urocortin 1 on colonic motility using an experimental model with isolated rat colon in which the blood flow and intestinal nerves were preserved. Furthermore, we assessed whether this effect was mediated by adrenergic or cholinergic nerves. METHODS: Colonic motility was measured in the proximal and distal parts of resected rat colon. The colon resected from the peritoneum was stabilized, and then urocortin 1 (13.8, 138, 277, and 1,388 pM) was administered via a blood vessel. Motility index was measured in the last 5 min of the 15 min administration of urocortin 1 and expressed as percentage change from baseline. Subsequently, the change in motility was measured by perfusing urocortin 1 in colons pretreated with phentolamine, propranolol, hexamethonium, atropine, or tetrodotoxin. RESULTS: At concentrations of 13.8, 138, 277, and 1,388 pM, urocortin 1 increased the motility of proximal colon (20.4+/-7.2%, 48.4+/-20.9%, 67.0+/-25.8%, and 64.2+/-20.9%, respectively) and the motility of distal colon (3.3+/-3.3%, 7.8+/-7.8%, 71.1+/-28.6%, and 87.4+/-32.5%, respectively). The motility induced by urocortin 1 was significantly decreased by atropine to 2.4+/-2.4% in proximal colon and 3.4+/-3.4% in distal colon (p<0.05). However, tetrodotoxin, propranolol, phentolamine, and hexamethonium did not inhibit motility. CONCLUSIONS: Urocortin 1 increased colonic motility and it is considered that this effect was directly mediated by local muscarinic cholinergic receptors.
Animals ; Colon/*drug effects/physiology ; Injections, Intravenous ; Male ; Muscle Contraction/drug effects ; Neurotransmitter Agents/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Cholinergic/chemistry/metabolism ; Urocortins/isolation & purification/*pharmacology

OBJECTIVEThe aim of this study is to investigate whether microwave exposure would affect the N-methyl-D-aspartate receptor (NMDAR) signaling pathway to establish whether this plays a role in synaptic plasticity impairment.

METHODS48 male Wistar rats were exposed to 30 mW/cm2 microwave for 10 min every other day for three times. Hippocampal structure was observed through H&E staining and transmission electron microscope. PC12 cells were exposed to 30 mW/cm2 microwave for 5 min and the synapse morphology was visualized with scanning electron microscope and atomic force microscope. The release of amino acid neurotransmitters and calcium influx were detected. The expressions of several key NMDAR signaling molecules were evaluated.

RESULTSMicrowave exposure caused injury in rat hippocampal structure and PC12 cells, especially the structure and quantity of synapses. The ratio of glutamic acid and gamma-aminobutyric acid neurotransmitters was increased and the intracellular calcium level was elevated in PC12 cells. A significant change in NMDAR subunits (NR1, NR2A, and NR2B) and related signaling molecules (Ca2+/calmodulin-dependent kinase II gamma and phosphorylated cAMP-response element binding protein) were examined.

CONCLUSION30 mW/cm2 microwave exposure resulted in alterations of synaptic structure, amino acid neurotransmitter release and calcium influx. NMDAR signaling molecules were closely associated with impaired synaptic plasticity.

Animals ; Gene Expression Regulation ; radiation effects ; Hippocampus ; cytology ; Microwaves ; Neuronal Plasticity ; radiation effects ; Neurons ; radiation effects ; Neurotransmitter Agents ; metabolism ; PC12 Cells ; Rats ; Receptors, N-Methyl-D-Aspartate ; genetics ; metabolism ; Signal Transduction ; physiology ; radiation effects ; Time Factors

As an important neurotransmitter, adenosine displays its functions by acting on the adenosine receptors. Recent studies have shown that the distribution, expression and balance among subtypes of adenosine receptors are closely related with cognitive activities, and changes of adenosine receptors play key roles in neurodegenerative disorders including Alzheimer's disease. It has been pointed out that prolonged activation of adenosine receptors by high level adenosine may lead to the disturbance of balance among adenosine receptor subtypes. This imbalance mainly performed as increased expression of A2a receptor and decreased expression of A1 receptor, and enhancement of the excitatory signals mediated by A2a receptor and weakened inhibitory signals mediated by A1 receptor. Changes of these two subtypes of adenosine receptors may lead to a lot of disorders of neurological activities which developed into dysfunction of cognition to the end. These findings imply that the potential of maintaining the balance among adenosine receptors on the treatment of AD would facilitate both the revealing of the mechanism and the cure of AD.
Adenosine ; physiology ; Alzheimer Disease ; physiopathology ; Humans ; Neurotransmitter Agents ; physiology ; Receptors, Purinergic P1 ; classification ; physiology

AIMTo investigate the effects of alpha1 and alpha2 receptors in the locus ceruleus (LC) on carotid baroreflex (CBR) resetting induced by intracerebroventricular injection (ICV) of histamine (HA).

METHODSThe left and right carotid sinus regions were isolated from the systemic circulation in 23 Sprague-Dawley rats anesthetized with pentobarbital sodium. The intracarotid sinus pressure (ISP) was altered in a stepwise manner. ISP-mean arterial pressure (MAP) relationship curve and its characteristic parameters were constructed by fitting to the logistic function with five parameters. The changes in CBR performance induced by ICV HA and the effects of pretreatment with alpha1 or alpha2 receptor antagonist into the LC on the responses of CBR to HA were examined.

RESULTSICV HA (60 micromol x L(-1) in 5 microl) significantly shifted the ISP-MAP relationship curve upwards (P < 0.05) and reduced the MAP range and maximum gain (P < 0.05). The pretreatment with phenoxybenzamine (PBZ, a selective antagonist of alpha1 receptor, 3 micromol x L(-1) in 500 nl) or yohimbine (YOH, a selective antagonist of alpha2 receptor, 2.5 micromol x L(-1) in 500 nl) into the LC could obviously intensify the above-mentioned changes in CBR performance induced by HA, but the intensive effect of PBZ was less remarkable than that of YOH (P < 0.05).

CONCLUSIONThe intracerebroventricular administration of HA results in a rapid resetting of CBR and a decrease in reflex sensitivity, and the functions of alpha1 and alpha2 receptors in the LC may attenuate CBR resetting induced by ICV HA. Furthermore, alpha2 receptor in the LC might play a more important role in regulating the responses of CBR to HA.

Animals ; Baroreflex ; drug effects ; physiology ; Carotid Sinus ; Histamine ; pharmacology ; Locus Coeruleus ; Male ; Rats ; Rats, Sprague-Dawley ; Receptors, Neurotransmitter

This study was designed to explore the innervation of autonomic nervous system and the distribution of receptors on pacemaker cell membrane in guinea pig left ventricular outflow tract (aortic vestibule). By using conventional intracellular microelectrode technique to record action potentials, autonomic neurotransmitters and antagonists were used to investigate the electrophysiological features and regularities of spontaneous activity of left ventricular outflow tract cells. Electrophysiological parameters examined were: maximal diastolic potential (MDP), amplitude of action potential (APA), maximal rate of depolarization (V(max)), velocity of diastolic depolarization (VDD), rate of pacemaker firing (RPF), 50% and 90% of duration of action potential (APD(50) and APD(90)). The results are listed below: (1) Perfusion with 100 mumol/L isoprenaline (Iso) resulted in a significant increase in V(max) (P <0.05), VDD, RPF, and APA (P <0.01), a notable decrease in MDP (P<0.05), and also a marked shortening in APD(50) (P<0.01). Pretreatment with Iso (100 mumol/L), propranolol (5 mumol/L) significantly decreased RPF and VDD (P<0.01), decreased APA, MDP and V(max) (P<0.01) notably, prolonged APD(50) (P<0.01) and APD(90) (P<0.05) markedly. (2) Application of 100 mumol/L epinephrine (E) resulted in a significant increase in VDD (P<0.05), RPF (P<0.001), V(max) (P<0.05) and APA (P<0.001), and a notable shortening in APD(50) and APD(90) (P<0.05). (3) Perfusion with 100 mumol/L norepinephrine (NE) led to a significant increase in VDD, RPF, APA and V(max) (P<0.05), and a marked shortening in APD(50) (P<0.05). Pretreatment with NE (100 mumol/L), phentolamine (100 mumol/L) significantly decreased RPF and VDD, MDP and APA (P<0.01), decreased V(max) notably (P<0.05), prolonged APD(50) and APD(90) markedly (P<0.01). (4) During perfusion with 10 mmol/L acetylcholine (ACh), VDD and RPF slowed down notably (P<0.05), APA decreased significantly (P<0.001), V(max) slowed down notably (P<0.01), APD50 shortened markedly (P<0.05), Atropine (10 mmol/L) antagonized the effects of ACh (10 mumol/L) on APD(50) (P<0.05). These results suggest that there are probably alpha-adrenergic receptor (alpha-AR), beta-adrenergic receptor (beta-AR) and muscarinic receptor (MR) on pacemaker cell membrane of left ventricular outflow tract in guinea pig. The spontaneous activities of left ventricular outflow tract cells are likely regulated by sympathetic and parasympathetic nerves.
Action Potentials ; drug effects ; Animals ; Aorta, Thoracic ; cytology ; physiology ; Electrophysiological Phenomena ; Female ; Guinea Pigs ; Heart Ventricles ; cytology ; Male ; Microelectrodes ; Neurotransmitter Agents ; physiology ; Receptors, Adrenergic, alpha ; physiology ; Receptors, Adrenergic, beta ; physiology ; Receptors, Muscarinic ; physiology ; Ventricular Function, Left ; physiology