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Neuropathic pain is a debilitating pathological condition that presents significant therapeutic challenges in clinical practice. Unfortunately, current pharmacological treatments for neuropathic pain lack clinical efficacy and often lead to harmful adverse reactions. As G protein-coupled receptors (GPCRs) are widely distributed throughout the body, including the pain transmission pathway and descending inhibition pathway, the development of novel neuropathic pain treatments based on GPCRs allosteric modulation theory is gaining momentum. Extensive research has shown that allosteric modulators targeting GPCRs on the pain pathway can effectively alleviate symptoms of neuropathic pain while reducing or eliminating adverse effects. This review aims to provide a comprehensive summary of the progress made in GPCRs allosteric modulators in the treatment of neuropathic pain, and discuss the potential benefits and adverse factors of this treatment. We will also concentrate on the development of biased agonists of GPCRs, and based on important examples of biased agonist development in recent years, we will describe universal strategies for designing structure-based biased agonists. It is foreseeable that, with the continuous improvement of GPCRs allosteric modulation and biased agonist theory, effective GPCRs allosteric drugs will eventually be available for the treatment of neuropathic pain with acceptable safety.

Analgesic effect of oxysophoridine and its effect on brain GAT-1 in mice / 中国药理学通报

Aim Tostudytheanalgesiceffectofoxyso-phoridine (OSR)on GABA transporter-1 (GAT-1 )mR-NA expression and its influence on GAT-1 expression inmice.Methods Formalintestwasusedtodetectthe analgesic effect of OSR(iv).Immunohistochemis-try was taken to inspect the expression of GAT-1 in cerebral cortex and thalamus in mouse brain. The quantitative real-time PCR method was used to inspect the influence of OSR on GAT-1 mRNA expression of braininmice.Results OSR(500,250,125mg· kg-1 ,iv ) could significantly increase the foot-licking latency.OSR(500 mg·kg-1,ip)could significantly decrease the number of GAT-1 immuopositive cells incerebral cortex and thalamus in mouse brain,and re-duce GAT-1 mRNA expression in brain(P<0. 01,P<0.05)intheformalintest.Conclusion OSRhasa significant analgesic effect,and its analgesic mecha-nism is related to the GAT-1 expression in mouse brain.

Study on the Diastolic Effect and Mechanism of Hui Medicine Hexin Oil Solution on Isolated Thoracic Aor-tic Vascular Rings of Rats / 中国药房

OBJECTIVE:To study the diastolic effect and mechanism of Hui medicine Hexin oil solution on isolated thoracic aortic vascular rings of rats,and provide reference for its treatment for cardiovascular diseases. METHODS:Thoracic aortic vascu-lar rings of rats were taken and then soaked in Kelvin's nutrient solution(K-H). Using 1×10-6 mol/L norepinephrine(PE)or 60 mmol/L potassium chloride (KCl) for inducing the contraction of vascular rings,biological signal acquisition and analysis system was used to determine the diastolic effect and mechanism of Hexin oil solution with concentrations of 0.0204,0.0408,0.0612, 0.0816,0.1020 mg/mL on vascular rings,and diastolic rate was calculated. After culturing vascular rings by 0.1 mmol/L nitric ox-ide synthase inhibitor L-nitro-arginine methyl ester (L-NAME),cyclooxygenase inhibitor indomethacin (INDO),and potassium ion channel blocker glibenclamide(Gli)for 20 min,the diastolic effects of above-mentioned 5 mass concentrations of Hexin oil so-lution on the contraction of vascular rings pre-contracted by PE were determined,and diastolic rate was calculated. The test was based on K-H solution as blank control. RESULTS:Compared with blank control,Hexin oil solution with concentration of 0.0204-0.1020 mg/mL had obvious diastolic effect on the contraction of vascular rings induced by PE and KCl (P<0.05 or P<0.01), showing concentration-dependent relationship. INDO pre-treatment can relieve the diastolic effect of Hexin oil solution on vascular rings pre-contracted by PE;and compared with blank control group,the diastolic rate had no statistical significance (P>0.05). While the pre-treatment of Gli,L-NAME did not affect the diastolic effect of Hexin oil solution on vascular rings pre-contracted by PE;and compared with blank control group,diastolic rate was obviously increased(P<0.05 or P<0.01). CONCLUSIONS:Hex-in oil solution can concentration-dependently conduct the relaxation of thoracic aortic vascular rings pre-contracted by PE,KCl. The mechanism may be associated with activation of cyclooxygenase pathway.

Study on the Diastolic Effect and Mechanism of Hui Medicine Hexin Oil Solution on Isolated Thoracic Aor-tic Vascular Rings of Rats / 中国药房

OBJECTIVE:To study the diastolic effect and mechanism of Hui medicine Hexin oil solution on isolated thoracic aortic vascular rings of rats,and provide reference for its treatment for cardiovascular diseases. METHODS:Thoracic aortic vascu-lar rings of rats were taken and then soaked in Kelvin's nutrient solution(K-H). Using 1×10-6 mol/L norepinephrine(PE)or 60 mmol/L potassium chloride (KCl) for inducing the contraction of vascular rings,biological signal acquisition and analysis system was used to determine the diastolic effect and mechanism of Hexin oil solution with concentrations of 0.0204,0.0408,0.0612, 0.0816,0.1020 mg/mL on vascular rings,and diastolic rate was calculated. After culturing vascular rings by 0.1 mmol/L nitric ox-ide synthase inhibitor L-nitro-arginine methyl ester (L-NAME),cyclooxygenase inhibitor indomethacin (INDO),and potassium ion channel blocker glibenclamide(Gli)for 20 min,the diastolic effects of above-mentioned 5 mass concentrations of Hexin oil so-lution on the contraction of vascular rings pre-contracted by PE were determined,and diastolic rate was calculated. The test was based on K-H solution as blank control. RESULTS:Compared with blank control,Hexin oil solution with concentration of 0.0204-0.1020 mg/mL had obvious diastolic effect on the contraction of vascular rings induced by PE and KCl (P<0.05 or P<0.01), showing concentration-dependent relationship. INDO pre-treatment can relieve the diastolic effect of Hexin oil solution on vascular rings pre-contracted by PE;and compared with blank control group,the diastolic rate had no statistical significance (P>0.05). While the pre-treatment of Gli,L-NAME did not affect the diastolic effect of Hexin oil solution on vascular rings pre-contracted by PE;and compared with blank control group,diastolic rate was obviously increased(P<0.05 or P<0.01). CONCLUSIONS:Hex-in oil solution can concentration-dependently conduct the relaxation of thoracic aortic vascular rings pre-contracted by PE,KCl. The mechanism may be associated with activation of cyclooxygenase pathway.

Effect of oxymatrine on CaMKII expression in sciatic nerve ligation-induced neuropathic pain in mice / 中国药理学通报

Aim To observe the analgesic effect of oxymatrine(OMT)and its mechanism.Methods A peripheral mononeuropathy was produced in adult mice by placing loosely constrictive ligatures around the common sciatic nerve.The antinociceptive effects of the OMT were assessed in mechanical allodynia and cold allodynia tests.The CAMKII inhibitor KN-93 and AIP were adopted to investigate the influence of OMT on the analgesic effect and analyze its analgesic mecha-nisms.Western blot was used to evaluate the expres-sions of tCaMKII and pCaMKII protein.Results The intraperitoneal administration of OMT (1 60,80 mg· kg -1 )increased the paw withdrawal threshold in the mechanical allodynia test (P <0.05 ),OMT (1 60, 80,40 mg·kg -1 ,ip)remarkably decreased the paw lifts in the cold allodynia test (P <0.05).Ith KN-93 (1 .25 μg/site),AIP (0.02 μg/site)significantly en-hanced the analgesic effect of OMT (35 mg·kg -1 ) (P <0.01 ).Protein expression of pCaMKII was de-creased by OMT(1 60 mg·kg -1 ).Conclusion OMT has significant protective effects on chronic constriction injury(CCI)in mice,and the effective mechanism of OMT inhibits the expression of CaMKII receptor.

Protective effects and mechanisms of OSR on primary cultured hippocampus neurons subjected to anoxic injury in neonatal rat / 中国中药杂志

<p><b>OBJECTIVE</b>To investigate the protective effects of oxysophoridine (OSR) on primary cultured hippocampus neurons subjected to anoxia injury in neonatal rats and its mechanism.</p><p><b>METHOD</b>The model of anoxia injury of hippocampus neurons in neonatal rats were primarily cultured in vitro by physical oxygen deficiency using glucose-free culture fluid. The survival rate of neurons, the leaking rate of lactate dehydrogenase (LDH), the intracellular contents of malondialdehyde (MDA) and nitric oxide (NO), the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) and nitric oxide synthase (NOS) were measured. The intracellular free calcium concentration ([Ca2+]i) in hippocampus neurons were detected with Ca(2+)-sensitive dual wavelength fluorescence spectrophotometer.</p><p><b>RESULT</b>Neuron death occurred in the anoxia injury model group with increase of LDH leaking rate, the contents of NO, MDA, intracellular [Ca2+] and the elevated activity of NOS while decreased activities of SOD and GSH-PX. The hippocampus neurons subjected to anoxia injury were alleviated in OSR (0.625, 5, 10 microg x L(-1)) group.</p><p><b>CONCLUSION</b>OSR has significant protective effects on hippocampus neurons subjected to anoxic injury. The mechanism of its protective effect may relate to its reduction of calcium overload and against oxidation injury.</p>

Effect of oxysophoridine on electric activities and its power spectrum of reticular formation in rats / 中国中药杂志

<p><b>OBJECTIVE</b>To observe the effect of oxysophoridine (OSR) on the EEG and its power spectrum of reticulum formation in mesencephalon of anaesthetized rat.</p><p><b>METHOD</b>Utilizing the technique of brain stereotactic apparatus, electrodes were implanted into reticulum formation of mesencephalon. Monopolar lead and computerized FFT technique were employed to record and analyse the index of EEG, power spectrum and frequency distribution in order to study the effect of oxysophoridine on the bioelectricity change of mesencephalon reticulum formation in rats.</p><p><b>RESULT</b>After administrating(icy) with oxysophoridine at the dose of 2.5,5, 10 mg/rat, the EEG of mesencephalon reticulum formation mainly characterized with low amplitude and slow waves accompanied by spindle-formed sleeping waves with a significant decrease of total power of EEG (P < 0.05) while the ratio of theta, alpha waves increased in total frequency of rats (P < 0.05).</p><p><b>CONCLUSION</b>Oxysophoridine possesses central inhibitory effects and its inhibitory mechanism may associate with the reduction of bioelectricity in mesencephalon reticulum formation. Mesencephalon reticulum formation may serve as one part of the structure serving as the circuit conducting the central inhibitory effect of oxysophoridine. [Key words] oxysophoridine; reticulum formation; electroencephalogram (EEG) ; rats</p>

The effect of oxysophoridine on electric activities and its power spectrums of cerebral frontal cortex in rats / 中国药理学通报

Aim To observe the effect of oxysophori-dine( OSR) on the EEG changes and its power spectrums of cerebral frontal cortex in anaesthetized rats. Methods With the equipment of brain stereotactic apparatus,electrode was implanted into frontal lobe of cerebral cortex in rats. Unipolar lead and computerized FFT technique were employed to record the index of EEG,power spectrum and frequency distributions to analyze the effect of OSR on the bioelectricity altera-tions of frontal lobe in cerebral cortexi in rats. Results Administrated( icv) with OSR at the dose of 2. 5,5, 10 mg/rat in rats,the EEG of frontal lobe of cerebral cortex was mainly featured by low amplitude and slow waves accompanied by spindle-formed sleeping waves with a significant decrease of total power of EEG( P

The analgesic action of oxysophoridine and its effect on the expression of PKC? in central nervous system of mice / 中国药理学通报

Aim To study the analgesic action of oxysophoridine and its effect on the expression of protein kinase C?(PKC?) in dorsal horn of spinal cord(it should be expressed as in dorsal horn of the spinal),cerebral cortex and thalamus of the mice.Methods Hot plate test was used to observe and analyze the analgesic strength and action position of OSR through iv and icv approaches,immunohistochemistry(SABC) was taken to inspect the expression of PKC? in dorsal horn of spinal cord(it should be expressed as in dorsal horn of the spinal),cerebral cortex and thalamus of the mice after administrating OSR.Results The foot-licking latencies of mice were prolonged both iv OSR(500、250、125 mg?kg-1)and icv OSR(100,50,25 mg?kg-1)in the hot plate test(P

Effects of sophoridine on central nervous system in mice / 中草药

Objective To boserve the effects of sophoridine on central nervous system in mice. Methods Behavioral methodology was employed to observe the effect of sophoridine on the normal mouse autonomic activities, and sleeping latency and sleep-lasting time of mice under threshold dosage of pentobarbital sodium. And to observe the synergistic effects of inducing convulsion between sophoridine and pentylenetetrazol, nicotin, strychine, isoniazid, and picrotoxin by subthreshold dosage. Results Sophoridine ip administrated (10 and 20 mg/kg) made the autonomic activities of mice suppressed by the rate of 66.9% and 76.6%, the sleeping latency of mice given pentobarbital sodium (40 mg/kg) prolonged, and sleeping time shortened (P