The regulatory effect of morphine postconditioning in left stellate ganglion on remodeling after myocardial infarction / 中国药理学通报

Aim To investigate the regulatory effect of morphine postconditioning in the LSG on remodeling after myocardial infarction. Methods SD rats were randomly divided into four groups: sham operation group (Sham), myocardial infarction group (MI), myocardial infarction + saline group (Control) and myocardial infarction + morphine postconditioning group (MI + Morphine) . The rat MI model was constructed by ligating the left anterior descending coronary artery, and then morphine was given to the LSG by percutaneous posterior approach. After four weeks, the changes of cardiac function in rats were detected by ultrasound. Masson staining was used to detect fibrosis changes; the expression of Collagen I and Collagen III protein was detected by Western blot. The mRNA expression of ANP and BNP was detected by RT-qPCR. The expression of JJLOR in LSG was detected by immunofluorescence. The concentration of catecholamine in plasma and myocardial tissue was detected by ELISA. Results Compared with the sham group, the cardiac function of the MI group was significantly impaired, the myocardial tissue showed significant fibrosis changes, and the concentration of catecholamine in plasma and myocardial tissue significantly increased. Compared with the control group, the MI + Morphine group reduced myocardial fibrosis collagen deposition in rats after MI, inhibited the expression of ANP and BNP in myocardial tissue, reduced the concentration of catecholamine, and improved the cardiac function of MI rats. Immunofluorescence results showed that JJLOR was expressed in LSG after MI and increased after morphine postconditioning. Conclusions This study shows that morphine postconditioning in the LSG has a protective effect on myocardial remodeling after myocardial infarction. The mechanism may be related to the activation of JJLOR in the LSG by morphine and the reduction of catecholamine release from sympathetic nerve endings.

Bispecific sigma-1 receptor antagonism and mu-opioid receptor partial agonism: WLB-73502, an analgesic with improved efficacy and safety profile compared to strong opioids

Opioids are the most effective painkillers, but their benefit-risk balance often hinder their therapeutic use. WLB-73502 is a dual, bispecific compound that binds sigma-1 (S1R) and mu-opioid (MOR) receptors. WLB-73502 is an antagonist at the S1R. It behaved as a partial MOR agonist at the G-protein pathway and produced no/unsignificant β-arrestin-2 recruitment, thus demonstrating low intrinsic efficacy on MOR at both signalling pathways. Despite its partial MOR agonism, WLB-73502 exerted full antinociceptive efficacy, with potency superior to morphine and similar to oxycodone against nociceptive, inflammatory and osteoarthritis pain, and superior to both morphine and oxycodone against neuropathic pain. WLB-73502 crosses the blood-brain barrier and binds brain S1R and MOR to an extent consistent with its antinociceptive effect. Contrary to morphine and oxycodone, tolerance to its antinociceptive effect did not develop after repeated 4-week administration. Also, contrary to opioid comparators, WLB-73502 did not inhibit gastrointestinal transit or respiratory function in rats at doses inducing full efficacy, and it was devoid of proemetic effect (retching and vomiting) in ferrets at potentially effective doses. WLB-73502 benefits from its bivalent S1R antagonist and partial MOR agonist nature to provide an improved antinociceptive and safety profile respect to strong opioid therapy.

Research progress on analgesic effect and adverse drug reactions of opioid receptor agonist-antagonists / 中国药房

Opioid receptor agonist-antagonists are a class of drugs which have both agonistic and antagonistic effects on opioid receptors. These drugs already on the market mainly include pentazocine， butorphanol， nalbuphine， buprenorphine， dezocine and so on. Compared with pure opioid receptor agonists such as morphine and fentanyl， these drugs have strong analgesic effects， less addictive， and less side effects such as cough， itching and respiratory depression. Due to the different tendentious effects of opioid receptor agonists-antagonists among different endogenous opioid receptors （μ， κ， δ， etc.）， different receptors of subtypes can exhibit different or even opposite effects in terms of affecting emotions and drug dependence. Therefore， the rational use of these drugs can effectively reduce the occurrence of adverse reactions and drug abuse caused by opioid drugs. With the deepening of research on various endogenous opioid receptor subtypes and related drugs in the academic community， opioid receptor agonists- antagonists have broad application space and prospects in improving adverse reactions to opioid drugs and enhancing patient drug compliance.

Effect of bergapten on glucose and oxygen deprivation induced PC12 cell injury by regulating long non-coding RNA opioid receptor gene expression / 解剖学报

Objective To study whether bergapten (BG) protects PC12 cells from oxygen-glucose deprivation (OGD) induced cell injury by regulating long non-coding RNA (lncRNA) opioid receptor gene (Oprm1) expression. Methods PC12 cells were divided into control (Con) group, OGD group, OGD+ low concentration BG (BG-L) group, OGD+medium concentration BG (BG-M) group, OGD + high concentration BG (BG-H) group, OGD + pcDNA group, OGD+pcDNA-Oprm1 group, OGD+BG+si-NC group, OGD+BG+si-Oprm1 group. The malondialdehyde (MDA) content, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were measured by the kits. Cell apoptosis rate was analysed by flow cytometry. The expression level of Oprm1 was analysed by Real-time PCR. Results Compared with the Con group, the apoptosis rate and MDA content of PC12 cells in OGD group increased significantly, whereas Oprm1 expression, SOD and GSH-Px activity decreased significantly (P < 0. 05). Compared with the OGD group, the apoptosis rate and MDA content of PC12 cells in the OGD + BG-L group, OGD + BG-M group, OGD + BG-H group were significantly reduced, whereas the Oprm1 expression, SOD and GSH-Px activities increased significantly (P < 0. 05). Compared with the OGD+pcDNA group, the apoptosis rate and MDA content of the PC12 cells in the OGD+pcDNA-Oprm1 group reduced significantly, whereas the SOD and GSH-Px activities increased significantly (P<0. 05). Compared with the OGD+BG+si-NC group, the apoptosis rate and MDA content of PC12 cells in the OGD+BG+si-Oprm1 group increased significantly, whereas the SOD and GSH-Px activities decreased significantly (P < 0. 05). Conclusion Bergapten may alleviate OGD-induced PC12 cell injury, which is correlated to the up-regulation of lncRNA Oprm1 expression.

Research on mechanism of opioid receptors in pharmacological effects of ketamine / 中国药理学通报

Ketamine has been used clinically as an analgesic and anesthetic since 1970. Recently, it has been concerned due to its rapid and effective antidepressant effect. However, the psychiatric adverse reactions caused by ketamine such as addiction and hallucination limit its clinical application, yet the mechanism of the adverse reactions is still unclear. At present, it is generally believed that the pharmacological effects of ketamine are mainly mediated by N-methyl-D-aspartate acid (NMDA) receptors, but increasing numbers of research evidences suggest that the opioid receptor also play an important role in the pharmacological effects of ketamine. This review, based on the relevant literature published publicly in the past 20 years, summarizes the mechanisms of opioid receptors in the pharmacological effects of ketamine, such as anesthesia, analgesia, anti-depressant, anti-addiction and addiction, providing reference for revealing the mechanism of ketamine, and making beneficial exploration for solving the clinical side effects of ketamine.

Targeting Peripheral μ-opioid Receptors or μ-opioid Receptor-Expressing Neurons Does not Prevent Morphine-induced Mechanical Allodynia and Anti-allodynic Tolerance / 神经科学通报·英文版

The chronic use of morphine and other opioids is associated with opioid-induced hypersensitivity (OIH) and analgesic tolerance. Among the different forms of OIH and tolerance, the opioid receptors and cell types mediating opioid-induced mechanical allodynia and anti-allodynic tolerance remain unresolved. Here we demonstrated that the loss of peripheral μ-opioid receptors (MORs) or MOR-expressing neurons attenuated thermal tolerance, but did not affect the expression and maintenance of morphine-induced mechanical allodynia and anti-allodynic tolerance. To confirm this result, we made dorsal root ganglia-dorsal roots-sagittal spinal cord slice preparations and recorded low-threshold Aβ-fiber stimulation-evoked inputs and outputs in superficial dorsal horn neurons. Consistent with the behavioral results, peripheral MOR loss did not prevent the opening of Aβ mechanical allodynia pathways in the spinal dorsal horn. Therefore, the peripheral MOR signaling pathway may not be an optimal target for preventing mechanical OIH and analgesic tolerance. Future studies should focus more on central mechanisms.

Antinociception Induced by Moringa Stenopetela (Baker f.) Cufod. Leaves Extract and Possible Mechanisms of Action

Moringa stenopetala (Baker f.) Cufod., is an endemic species growing in the south of Ethiopia. M. stenopetala is often consumed as food and used in traditional medicine and it has also been traditionally used for relieving of pain in Ethiopia. This study aimed to investigate the antinociceptive effect and mechanisms of action of M. stenopetala leaves methanol extract in mice. The per-oral doses of 50, 100, and 200 mg/kg of M. stenopetala extract were tested for antinociceptive action by using hot-plate, tail-immersion, and writhing tests. The possible mechanisms of in the antinociceptive action were investigated by pre-treatment with 5 mg/kg naloxone (non-selective opioid antagonist), 1 mg/kg ketanserin (5-HT2A/2C receptor antagonist), and 1 mg/kg yohimbine (α2 adrenoceptor antagonist). The methanol extract of M. stenopetala showed antinociceptive effect in all tests. The significant involvement of 5-HT2A/2C receptors and α2 adrenoceptors in antinociception induced by M. stenopetala extract in the hot-plate and tail-immersion tests, as well as significant contribution of opioid receptors and α2 adrenoceptors in writhing test, were identified. In conclusion, these findings demonstrate that the methanol extract of M. stenopetala has potential in pain management. Thisstudywillcontributetonewtherapeuticapproachesandprovideguidancefornewdrug development studies.

Inhibition of activated K-opioid receptor to myocardical hypertrophy induced by ET-1 in neonatal rats by extracellular signal-regulated kinase pathway / 中国药理学通报

Aim To investigate the inhibitory effect of kappa-opioid receptor(κ-OR)stimulation on extracellular signal-regulated kinase pathway on ET-1-induced cardiomyocyte hypertrophy in vitro cultured myocardial cells from neonatal rats.Methods Myocardial cells of neonatal rats were cultured in vitro.The hypertrophic myocytes were induced by ET-1(10 nmol·L-1)before κ-OR agonist U50488H(1 μmol·L-1)was administered.The antihypertrophic effect of κ-OR stimulation was observed in the presence of U0126(1μmol·L-1), Ro-31-8220(50 nmol·L-1)and PTX(5 mg·L-1).The cardiomyocytes volume was measured by computer photographalysis system.The relative expression of ERK1/2 was determined by Western blot.The morphological changes in cardiomyocytes were observed under an inverted phase contrast microscope.The expression of mRNA of atrial natriuretic peptide(ANP)was determined by RT-PCR.Results Compared with normal control group, ET-1 could induced cardiomyocyte hypertrophy.Compared with ET-1 model group, U50488H(1 μmol·L-1)could obviously inhibit ET-1-induced increase of the cardiomyocytes volume, expression of ANPmRNA and expression of ERK1/2, which was similar to U0126(1 μmol·L-1)and Ro-31-8220(50 nmol·L-1); however, the inhibitory effects of U50488H were partly lost when preincubated with U0126(1 μmol·L-1)and Ro-31-8220(50 nmol·L-1); the inhibitory effects of U50488H, U0126(1 μmol·L-1)and Ro-31-8220(50 nmol·L-1)were lost when preincubated with NOR-BNI.Conclusion The stimulation of kappa-opiod can inhibit myocardial hypertrophy induced by ET-1, which is possibly via attenuating ERK1/2.

Electroacupuncture Attenuates Surgical Stress-Induced Reduction of T Lymphocytes through Modulation of Peripheral Opioid System / 中国结合医学杂志

OBJECTIVE@#To investigate the action mechanisms of electroacupuncture (EA) on postoperative immunosuppression.@*METHODS@#Male C57BL/6 mice (5`-7 weeks old) were randomly divided into: the sham injury group, the surgical trauma stressed group, the EA group [surgery + 2/100 Hz EA at Neiguan (PC 6)], and the EA+ Nal (surgery + EA + intraperitoneal injection of naloxone). Abdominal surgical trauma stress mice model was established. EA was performed on bilateral PC 6 acupoints by an EA apparatus (2/100 Hz) for 20 min once a day for 3 days. The mRNA expressions of MOR, DOR, and KOR in thymus and L3`-L5 dorsal root ganglions (DRG) were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and the protein expressions of MOR, DOR, and KOR in thymus were measured by Western blot. Flow cytometry assay was used to detect the levels of T lymphocyte subtypes in the peripheral blood.@*RESULTS@#Surgical trauma induced decreased the mRNA expression level of MOR in both thymus (P0.05). Furthermore, T lymphocyte population of CD3@*CONCLUSION@#EA may improve postoperative immunosuppression through the peripheral opioid system.

Mu-Opioid Receptors Expressed in Glutamatergic Neurons are Essential for Morphine Withdrawal / 神经科学通报·英文版

Although opioids still remain the most powerful pain-killers, the chronic use of opioid analgesics is largely limited by their numerous side-effects, including opioid dependence. However, the mechanism underlying this dependence is largely unknown. In this study, we used the withdrawal symptoms precipitated by naloxone to characterize opioid dependence in mice. We determined the functional role of mu-opioid receptors (MORs) expressed in different subpopulations of neurons in the development of morphine withdrawal. We found that conditional deletion of MORs from glutamatergic neurons expressing vesicular glutamate transporter 2 (Vglut2) largely eliminated the naloxone-precipitated withdrawal symptoms. In contrast, conditional deletion of MORs expressed in GABAergic neurons had a limited effect on morphine withdrawal. Consistently, mice with MORs deleted from Vglut2 glutamatergic neurons also showed no morphine-induced locomotor hyperactivity. Furthermore, morphine withdrawal and morphine-induced hyperactivity were not significantly affected by conditional knockout of MORs from dorsal spinal neurons. Taken together, our data indicate that the development of morphine withdrawal is largely mediated by MORs expressed in Vglut2 glutamatergic neurons.

Mu-Opioid Receptors Expressed in Glutamatergic Neurons are Essential for Morphine Withdrawal / 神经科学通报·英文版

Although opioids still remain the most powerful pain-killers, the chronic use of opioid analgesics is largely limited by their numerous side-effects, including opioid dependence. However, the mechanism underlying this dependence is largely unknown. In this study, we used the withdrawal symptoms precipitated by naloxone to characterize opioid dependence in mice. We determined the functional role of mu-opioid receptors (MORs) expressed in different subpopulations of neurons in the development of morphine withdrawal. We found that conditional deletion of MORs from glutamatergic neurons expressing vesicular glutamate transporter 2 (Vglut2) largely eliminated the naloxone-precipitated withdrawal symptoms. In contrast, conditional deletion of MORs expressed in GABAergic neurons had a limited effect on morphine withdrawal. Consistently, mice with MORs deleted from Vglut2 glutamatergic neurons also showed no morphine-induced locomotor hyperactivity. Furthermore, morphine withdrawal and morphine-induced hyperactivity were not significantly affected by conditional knockout of MORs from dorsal spinal neurons. Taken together, our data indicate that the development of morphine withdrawal is largely mediated by MORs expressed in Vglut2 glutamatergic neurons.

Mu-opioid receptors in the paraventricular nucleus regulate ejaculatory behaviors via the sympathetic nerve system in male rats / 中华男科学杂志

Objective@#To explore the effects of the mu-opioid receptor (MOR) in the paraventricular nucleus (PVN) on the ejaculatory behaviors of male rats and its potential mechanisms.@*METHODS@#Male SD rats with normal ejaculation ability were mated with female ones in hormone-induced estrus. After bilateral PVN microinjection of D-Ala-2-Me-Phe-4-Gly-ol enkephalin (DAGO) or D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) with an inserted catheter, the male animals were observed for mount latency (ML), mount frequency (MF), intromission latency (IL), intromission frequency (IF), ejaculation latency (EL), ejaculation frequency (EF), post-ejaculation interval (PEI), and intromission ratio (IR). The lumbar sympathetic nerve activity (LSNA) of the rats was recorded using the PowerLab data acquisition hardware device, and the levels of norepinephrine (NE) in the peripheral plasma were measured by ELISA following microinjection of saline or different doses of DAGO or CTAP.@*RESULTS@#Neither CTAP nor DGAO significantly affected the ML of the male rats (P > 0.05). DGAO remarkably increased IF (P < 0.01) and MF (P < 0.01), prolonged IL (P < 0.01), EL (P < 0.01) and PEI (P < 0.01), and reduced EF (P <0.01) and IR (P < 0.05). On the contrary, CTAP markedly decreased IF (P < 0.01) and MF (P < 0.01), shortened IL (P < 0.01), EL (P < 0.01) and PFI (P < 0.01), and elevated EF (P < 0.01) and IR (P < 0.01). Additionally, DAGO decreased LSNA in a dose-dependent manner and reduced the NE level in the peripheral plasma. CTAP, however, not only offset the effects of DAGO on LSNA, but also significantly increased LSNA.@*CONCLUSIONS@#MOR in PVN inhibits ejaculatory behaviors in male rats by weakening LSNA, which has provided some theoretical evidence for the use of highly selective opioids in the treatment of premature ejaculation.

Role of ZHX2 in regulating dorsal root ganglion μ-opioid receptor expression in mice with peripheral nerve injuryinduced pain hypersensitivity / 南方医科大学学报

OBJECTIVE@#To investigate the role of zinc-fingers and homeoboxes 2 (ZHX2) in regulating μ-opioid receptor expression in the dorsal root ganglion (DRG) in mice with peripheral nerve injury-induced pain hypersensitivity.@*METHODS@#Forty-eight male adult C57BL6J mice were randomized into 4 groups and subjected to chronic constriction injury (CCI) of the sciatic nerve or sham operation followed by microinjection of a specific small interfering RNA (siRNA) of ZHX2 or a negative control siRNA sequence (siNC) into the DRG. Seven days later, the mice were examined for changes in the hind paw withdrawal frequency (PWF), after which the DRG tissue was collected for detecting the expressions of μ-opioid receptor at the mRNA and protein levels using RT-qPCR and Western blotting. In another experiment, the DRG tissues were collected from 6 mice (21-day-old) for primary culture of the DRG neurons, which were transfected with ZHX2 siRNA or the siNC to observe the changes in the expressions of ZHX2 and μ-pioid receptor.@*RESULTS@#Microinjection of ZHX2 siRNA into the ipsilateral L3 and L4 DRGs significantly reversed CCI-induced μ-pioid receptor downregulation in the injured DRG and alleviated CCI-induced mechanical allodynia in the mice. In the cell experiment, ZHX2 knockdown obviously upregulated the mRNA and protein expressions of opioid receptor in the primary cultured DRG neurons.@*CONCLUSIONS@#ZHX2 knockdown in the DRG reverses CCI-induced down-regulation of μ opioid receptor to alleviate periphery nerve injury-induced pain hypersensitivity in mice.

Anti-nociceptive effect of patchouli alcohol: Involving attenuation of cyclooxygenase 2 and modulation of mu-opioid receptor / 中国结合医学杂志

OBJECTIVE@#To explore the anti-nociceptive effect of patchouli alcohol (PA), the essential oil isolated from Pogostemon cablin (Blanco) Bent, and determine the mechanism in molecular levels.@*METHODS@#The acetic acid-induced writhing test and formalin-induced plantar injection test in mice were employed to confirm the effect in vivo. Intracellular calcium ion was imaged to verify PA on mu-opioid receptor (MOR). Cyclooxygenase 2 (COX2) and MOR of mouse brain were expressed for determination of PA's target. Cellular experiments were carried out to find out COX2 and MOR expression induced by PA.@*RESULTS@#PA significantly reduced latency period of visceral pain and writhing induced by acetic acid saline solution (P<0.01) and allodynia after intra-plantar formalin (P<0.01) in mice. PA also up-regulated COX2 mRNA and protein (P<0.05) with a down-regulation of MOR (P<0.05) both in in vivo and in vitro experiments, which devote to the analgesic effect of PA. A decrease in the intracellular calcium level (P<0.05) induced by PA may play an important role in its anti-nociceptive effect. PA showed the characters of enhancing the MOR expression and reducing the intracellular calcium ion similar to opioid effect.@*CONCLUSIONS@#Both COX2 and MOR are involved in the mechanism of PA's anti-nociceptive effect, and the up-regulation of the receptor expression and the inhibition of intracellular calcium are a new perspective to PA's effect on MOR.

Electroacupuncture intervention relieves pain possibly by promoting MOR endocytosis in locus coeruleus in bone cancer pain rats with morphine tolerance / 针刺研究

OBJECTIVE: To observe the effect of electroacupuncture (EA) on pain behavior and expression of µ-opioid receptor (MOR) and Rab5 (an important protein molecule for internalization of MOR) in the locus coeruleus (LC) region in bone cancer pain (BCP) rats with morphine tolerance (MT), so as to explore its mechanisms underlying improvement of BCP and MT. METHODS: The present study included two parts. In the first part, 23 female SD rats were randomized into sham BCP (n＝6), BCP (n＝9) and BCP＋MT (n＝8) groups, and in the second part, 61 female SD rats were randomized into 5 groups: sham BCP (n＝11), BCP (n＝11), BCP＋MT (n＝13), BCP＋MT＋EA (n＝13) and BCP＋MT＋sham EA (n＝13). The BCP morphine tolerance (BCP＋MT) model was established by injection of 10 µL of human Walker 256 breast cancer cells (MRMT-1 breast cancer cells, 1 x104 cells/µL) into the bone marrow cavity at the upper part of the left tibia and intraperitoneal injection of morphine hydrochloride (10 mg/kg, once per 12 h, for 11 successive days). On day 21 after inoculation, EA (2 Hz/100 Hz, 0.5－1.5 mA, increasing 0.5 mA every 10 min) was began to applied to bilateral "Zusanli" (ST30) and "Kunlun" (BL60) immediately after the first intraperitoneal injection of morphine. The treatment was performed for 30 min every time, once daily for 7 successive days. The paw withdrawal threshold (PWT) was detected before and 10, 11, 21, 22, 24, 26 and 28 days after inoculation. The immunoactivity of MOR and Rab5 proteins in the LC region was detected by immunofluorescence histochemistry. RESULTS: In the first part of the study, at the 10th day after inoculation of cancer cells, the PWT of the BCP and BCP＋MT groups was significantly lower than that of the sham BCP group (P0.05) but significantly lower than that of the sham BCP group (P0.05). CONCLUSION: EA intervention can relieve pain and MT in bone cancer pain rats with MT, which may be related to its effects in increasing MOR expression and promoting endocytosis of MOR in LC region.

Role of On-cells and Off-cells in the rostral ventromedial medulla in pain modulation / 上海交通大学学报（医学版）

The rostral ventromedial medulla is one of the key structures in descending pain modulation system. It receives inputs from the thalamus, the periaqueductal gray, and parabrachial nucleus, and sends descending projections through the dorsolateral funiculus and ventrolateral funiculus to the spinal dorsal horns. The rostral ventromedial medulla is thought to be the final relay in descending modulation of pain. The neurons in this region can be classified into On-cells, Off-cells and Neutral cells according to the changes in the firing activity before tail flick. This review mainly focuses on pain modulation functions and potential analgesia mechanisms of On-cells and Off-cells.

Progress in evaluation methods and mechanisms of opioid receptor-mediated side effects / 中国药理学通报

K opioid receptor agonists produce potent antinociception without morphine-like side effects. However, selective K opioid receptor agonists exhibit severe dysphoria, limiting their clinical use. Developing new K agonists with less CNS side effects appears to offer some advantages over u, agonist for the treatment of pain. In this review, we summarize the representative analgesics targeting K opioid receptors in the clinic and introducethe latest progress of methodology and underlying mechanism of K receptor-mediated dysphoria.

Antitussive effect and mechanism study of effective fractions from Sauropus rostratus / 中草药

Objective: To study the antitussive effect of Sauropus spatulifolius, screen the active part of its antitussive effect, and study its antitussive mechanism. Methods The acute toxicity of different extraction sites of S. spatulifolius were studied by modified Karber’s method; The model was made with ammonia liquor to induce cough. The spray time that caused half of the mice to cough was calculated by sequential method with aim to screen the active sites. Capsaicin was used to induce cough, and the mechanism of action of extracts from various parts of S. spatulifolius on opioid receptor and ATP-sensitive potassium channel (KATP) of mice was explored. Results The LD50 of 75% ethanol, ethyl acetate, n-butanol, and 95% ethanol extracts was 7.30, 17.00, 69.68, and 75.88 g/kg, respectively; The maximum tolerance dose (MTD) of petroleum ether extracts was 117.71 g/kg; Extracts from 75% ethanol and ethyl acetate had antitussive effects, and its antitussive effect was related to opioid receptor and KATP pathway. Conclusion The fractions from 75% ethanol and ethyl acetate are the active parts of S. spatulifolius for relieving cough, and its antitussive mechanism is related to the KATP pathway and opioid receptors in the excited central system.

Advances of Butorphanol in Clinical Research / 中国医师进修杂志

Pain is a common and crucial problem in clinical practice, because it has a profound influence on patients in perioperative period. Butorphanol, among plenty of analgesics, is widely used in clinical trials for its various advantages and better analgesic effects. As a typical agonist-antagonist opioid analgesic agent, butorphanol, however, shows different clinical manifestations with different affinity for opioid receptors 25∶4∶1 (κ∶μ∶δ). Besides, butorphanol provides remarkable analgesic and sedative effect in preemptive analgesia, induction and recovery period in general anesthesia, and postoperative analgesia And it could be as a adjuvant to local anaesthesia either. Compared with other opioid drugs, butorphanol is less likely to have side effect on respiratory depression. In addition, its physical dependence is extremely low.

Can oliceridine (TRV130), an ideal novel µ receptor G protein pathway selective (µ-GPS) modulator, provide analgesia without opioid-related adverse reactions?

All drugs have both favorable therapeutic and untoward adverse effects. Conventional opioid analgesics possess both analgesia and adverse reactions, such as nausea, vomiting, and respiratory depression. The opioid ligand binds to µ opioid receptor and non-selectively activates two intracellular signaling pathways: the G protein pathway induce analgesia, while the β-arrestin pathway is responsible for the opioid-related adverse reactions. An ideal opioid should activate the G protein pathway while deactivating the β-arrestin pathway. Oliceridine (TRV130) has a novel characteristic mechanism on the action of the µ receptor G protein pathway selective (µ-GPS) modulation. Even though adverse reactions (ADRs) are significantly attenuated, while the analgesic effect is augmented, the some residual ADRs persist. Consequently, a G protein biased µ opioid ligand, oliceridine, improves the therapeutic index owing to increased analgesia with decreased adverse events. This review article provides a brief history, mechanism of action, pharmacokinetics, pharmacodynamics, and ADRs of oliceridine.