Zehui Gong

Levo-tetrahydropalmatine attenuates oxycodone-induced conditioned place preference in rats

Levo-tetrahydropalmatine (l-THP) is an alkaloid purified from the Chinese herb corydalis and stephania and is contained in many traditional Chinese herbal preparations. Our previous studies demonstrated the ability of l-THP to inhibit locomotor stimulation and physical dependence induced by oxycodone in mice and rats. The present study was designed to evaluate effects of l-THP on reward of oxycodone using conditioned place preference assay. Oxycodone (0.32-5.0 mg/kg) induced the development of conditioned place preference in rats. Furthermore, oxycodone (2.5 mg/kg) induced the increased phosphorylation of CREB and ERK in nucleus accumbens and hippocampus, but not in prefrontal cortex. l-THP (6.25-18.50 mg/kg) per se was not able to induce conditioned place preference or conditioned place aversion. l-THP co-administered with oxycodone during the conditioning sessions partly abolished the development of oxycodone-induced conditioned place preference in rats. Furthermore, l-THP inhibited the increased phosphorylation of ERK and CREB in nucleus accumbens and hippocampus of rats. All these results suggest that l-THP can inhibit oxycodone-induced psychological dependence by affecting phosphorylation of CREB and ERK in nucleus accumbens and hippocampus of rats. Together, the present data, combined with previous finding, support the potential use of l-THP for treatment of oxycodone addiction.

Effects of l-tetrahydropalmatine on locomotor sensitization to oxycodone in mice.

AbstractAim:Recent studies have shown that l-tetrahydropalmatine (l-THP), an active component of Corydolis yanhusuo, can inhibit the development of the conditional place preference induced by opioid receptor agonists, but the effects of l-THP on locomotor sensitivity induced by opioid receptor agonists have not beendocumented. In the present study, the effects of l-THP on locomotor sensitization to oxycodone, which is an opioid receptor agonist, were studied.Methods:Mice treated daily for 7 d with 5 mg/kg oxycodone and challenged with the same dose after 5 days of washout showed locomotor sensitization. In order to study the effects of l-THP on locomotor sensitization induced by oxycodone, l-THP was administered at doses of 6.25, 12.5, and 18.75 mg/kg, 40 min prior to treatment of oxycodone.Results:l-THP per se did not affect the locomotor activity at the doses of 6.25, 12.5, and 18.75 mg/kg, but could antagonize the hyperactivity induced by oxycodone (5 mg/kg). Co-administration of l-THP (18.75 mg/kg), 40 min prior to oxycodone, could inhibit the development of sensitization to oxycodone. In addition, l-THP (6.25, 12.5, and 18.75 mg/kg, ig) dose-dependently prevented the expression of oxycodone sensitization.Conclusion:These results suggested that l-THP could attenuate the locomotor-stimulating effects of oxycodone and inhibit the development and expression of oxycodone behavioral sensitization.

Effect of thienorphine on intestinal transit and isolated guinea-pig ileum contraction

AIM To evaluate the effect of thienorphine on small intestinal transit in vivo and on guinea-pig ileum (GPI) contraction in vitro. METHODS The effects of thienorphine on intestinal transit were examined in mice and in isolated GPI. Buprenorphine and morphine served as controls. The distance traveled by the head of the charchol and the total length of the intestine were measured in vivo. Gastrointestinal transit was expressed as a percentage of the distance traveled by the head of the marker relative to the total length of the small intestine. The isolated GPI preparations were connected to an isotonic force transducer and equilibrated for at least 1 h before exposure to drugs. Acetylcholine was used for muscle stimulation. RESULTS Thienorphine (0.005-1.0 mg/kg, ig) or buprenorphine (0.005-1.0 mg/kg, sc) dose-dependently significantly inhibited gut transit compared with saline. Thienorphine inhibited gut transit less than buprenorphine. The maximum inhibition by thienorphine on the intestinal transit was 50%-60%, whereas the maximum inhibition by morphine on gut transit was about 100%. Thienorphine also exhibited less inhibition on acetylcholine-induced contraction of GPI, with a maximum inhibition of 65%, compared with 93% inhibition by buprenorphine and 100% inhibition by morphine. Thienorphine induced a concentration-dependent decrease in the basal tonus of spontaneous movement of the GPI, the effect of which was weaker than that with buprenorphine. The duration of the effect of thienorphine on the GPI was longer than that with buprenorphine. CONCLUSION Thienorphine had less influence, but a longer duration of action on GPI contraction and moderately inhibited intestinal transit.

CHP1002, a novel andrographolide derivative, inhibits pro-inflammatory inducible nitric oxide synthase and cyclooxygenase-2 expressions in RAW264.7 macrophages via up-regulation of heme oxygenase-1 expression

Andrographolides, a type of diterpene lactone, are widely known to have anti-inflammatory and anti-oxidative properties. CHP1002, a synthetic derivative of andrographolide, has similar anti-inflammatory action in mouse ear swelling test and rat paw edema test. In the present study, the mechanism of anti-inflammatory effects of CHP1002 was investigated in RAW264.7 macrophages. CHP1002 potently suppressed inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expressions in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. CHP1002 reduced the production of iNOS-derived nitric oxide (NO) and COX-2-derived prostaglandin E2 (PGE2). CHP1002 induced heme oxygenase-1 (HO-1) expression via activation of extracellular signal-regulated kinase (ERK) and NF-E2 related factor 2 transcription factor (Nrf2). Down-regulation of LPS-induced iNOS and COX-2 expressions was partially reversed by the HO-1 inhibitor zinc protoporphyrin (ZnPP). In addition, CHP1002 significantly attenuated LPS-induced TNF-α, IL-1β and IL-6 production. CHP1002 effectively induced HO-1 and was capable of inhibiting some macrophage-derived pro-inflammatory mediators, which may be closely correlated with its anti-inflammatory action.

Chicago sky blue 6B, a vesicular glutamate transporters inhibitor, attenuates methamphetamine-induced hyperactivity and behavioral sensitization in mice

Several lines of evidence demonstrate that glutamatergic system plays an important role in drug addiction. The present study was designed to investigate the effects of Chicago sky blue 6B (CSB6B), a vesicular glutamate transporters (VGLUTs) inhibitor, on methamphetamine (METH)-induced behaviors in mice. Mice were induced behavioral sensitization to METH by subcutaneous injection of 1mg/kg METH once daily for 7 days and then challenged with 1mg/kg METH in 14th day. Intracerebroventricular administration of CSB6B (7.5μg) 2.5h prior to METH was to observe its effects on METH -induced behavioral sensitization. Our results showed that the expressions of behavioral sensitization were significantly attenuated by intracerebroventricular administration of CSB6B 2.5h prior to METH either during the development period or before methamphetamine challenge in mice, while CSB6B itself had no effect on locomotor activity. Meanwhile, pretreatment of CSB6B also attenuated hyperactivity caused by a single injection of METH in mice. These results demonstrated that CSB6B, a VGLUTs inhibitor, attenuated acute METH-induced hyperactivity and chronic METH-induced behavioral sensitization, which indicated that VGLUTs were involved in the effect of chronic METH-induced behavioral sensitization and may be a new target against the addiction of METH.

The antinociceptive effects of intracerebroventricular administration of Chicago sky blue 6B, a vesicular glutamate transporter inhibitor.

Accumulating evidence suggests that vesicular glutamate transporters (VGLUTs), which control the storage and release of glutamate, may play a role in pain processing. Chicago sky blue 6B (CSB6B), which is structurally related to glutamate, is a competitive VGLUT inhibitor without affecting plasma membrane transporters. The present study was designed to investigate the antinociceptive effects of CSB6B in a number of pain models. The hot-plate test was used as an acute thermal pain test. Inflammatory pain was evaluated using acetic acid writhing, formalin, and complete Freund’s adjuvant tests. Intracerebroventricular administration of CSB6B did not affect acute thermal pain responses in 50 or 55°C hot plate tests. However, CSB6B attenuated acetic acid-induced writhing in a dose-dependent and time-dependent manner. In addition, CSB6B reduced licking/biting behavior during the second phase, but not during the first phase, following an intraplantar injection of formalin. In the complete Freund’s adjuvant test, a significant attenuation of thermal hyperalgesia was also observed in CSB6B-treated mice. At antinociceptive doses, CSB6B did not affect mice spontaneous locomotor activity. The present study shows that pharmacological inhibition of VGLUT activity was sufficient to attenuate experimental inflammatory pain and suggests that regulation of VGLUTs might be a novel therapeutic strategy for the treatment of pain.

Inhibition of vesicular glutamate transporters contributes to attenuate methamphetamine-induced conditioned place preference in rats

Accumulating evidence suggests that glutamatergic system plays a crucial role in methamphetamine (METH) addiction. In the glutamatergic transmission, vesicular glutamate transporters (VGLUTs) are responsible for transporting glutamate into synaptic vesicles and affect the glutamate concentrations in the synaptic cleft. It is well documented that VGLUTs play an essential role in pathophysiology of several psychiatric and neurological diseases, however, whether VGLUTs also have a role in addiction caused by psychostimulant drugs is still unknown. The present study was underwent to investigate the effect of inhibition of VGLUTs on METH-induced induce conditioned place preference in rats. Rats were induced to conditioned place preference with METH (0.5, 1.0 and 2.0mg/kg) by intraperitoneal injection. Intracerebroventricular administration of 1.0 or 5.0μg Chicago sky blue 6B (CSB6B), a VGLUTs inhibitor, and 2.5h prior to METH was to observe its effect on METH-induced conditioned place preference in rats. The rats receiving METH showed stronger place preference at the dose of 1.0mg/kg than that of other doses. The intracerebroventricular administration of CSB6B (1.0, 5.0μg) 2.5h prior to the exposure to METH attenuated the acquisition of METH-induced conditioned place preference, while CSB6B itself had no effect on place preference. These results indicate that VGLUTs are involved in the effect of METH-induced conditioned place preference and may be a new target against METH addiction.

The effect of chronic thienorphine administration on long‐term potentiation and synaptic structure in rat hippocampus

Thienorphine is a new nonselective partial agonist of opioid receptors, which is currently under a Phase II clinical trial in China as a new treatment for opioid dependence. In this study, we compared the effect of thienorphine with morphine on long‐term potentiation (LTP) in the lateral perforant path (LPP)‐granule cell synapse of the rat dentate gyrus (DG). Furthermore, the effect of thienorphine on the synaptic structure of the CA1 hippocampal region and the expression of synaptophysin was investigated. Results indicated interesting differences between thienorphine and morphine on the modulation of hippocampal synaptic plasticity. Chronic thienorphine treatment facilitated LTP in the LPP‐DG cell synapses more than chronic morphine treatment. Morphometric measurement and analysis showed that chronic thienorphine administration decreased the length of the active zone and reduced the thickness of CA1 postsynaptic densities compared with the saline group (control), but were elevated compared with the morphine group. Furthermore, the expression of hippocampal synaptophysin was increased with chronic thienorphine administration but reduced with chronic morphine treatment. Taken together, our study clearly demonstrates that chronic thienorphine treatment enhances LTP, modulates hippocampal synaptic structure, and increases the expression of hippocampal synaptophysin. Therefore, further study is warranted to investigate thienorphine as a new treatment for opioid dependence. Synapse 67:779–785, 2013.

Spinal antinociception of synthetic omega-conotoxin SO-3, a selective N-type neuronal voltage-sensitive calcium channel blocker, and its effects on morphine analgesia in chemical stimulus tests in rodent.

SO-3, a novel Omega-superfamily conotoxin derived from Conus striatus, selectively inhibits N-type neuronal voltage-sensitive calcium channels. In current study, antinociception of SO-3 compared with MVIIA or morphine and its effects on morphine analgesia were investigated in rodent chemical stimulus tests after acute or repeated intrathecal administration. In mice acetic acid writhing test, similar to MVIIA, SO-3 caused dose- and time-dependent spinal antinociception with ED(50) of 0.25 microg/kg and t(1/2) of 4h, which was more potent and longer-acting than morphine. In rat formalin test after intrathecal bolus injection, SO-3 produced dose- and time-dependent antinociception by suppressing acute (ED(50), 1.79 microg/kg) and tonic phases (ED(50), 0.41 microg/kg), which was similar to MVIIA and approximately 10-fold potency and twice longer-acting of morphine in blocking tonic phase responses. After repeated intrathecal injections twice daily for 5 consecutive days, SO-3 produced analgesia without loss of potency whereas morphine produced analgesia tolerance in rat formalin test; further, SO-3 still produced potent analgesia in morphine-tolerant rats. SO-3 co-administered with morphine left-shift the dose-response curve of morphine in mice acetic acid writhing test and significantly potentiated morphine analgesia in rat formalin test. No changes in motor function were seen in mice or rats receiving antinociceptive doses of SO-3 whereas MVIIA caused motor dysfunction at doses of 1.0-2.0 microg/kg in rats. This study showed that (1) novel SO-3 produced potent and long-acting spinal antinociception without observable motor dysfunction, (2) SO-3 significantly potentiated morphine analgesia, (3) After repeated intrathecal administration, SO-3 produced neither tolerance nor cross-tolerance to morphine analgesia.

Effects of thienorphine on contraction of the guinea pig sphincter of Oddi, choledochus and gall bladder.

Opioid analgesics are widely believed to cause spasm of the bile duct sphincter and so impede bile flow. Thienorphine is a partial opioid agonist that is a good candidate for the treatment of opioid dependence; however, to date, no studies have reported the effects of thienorphine on the function of the biliary tract. This study examined the in vivo effects of thienorphine on the guinea pig isolated sphincter of Oddi, choledochus and gall bladder and on bile flow. The area under the curve (AUC) of isolated sphincter of Oddi was not influenced by thienorphine or buprenorphine, whereas morphine increased the AUC of the isolated sphincter of Oddi in a concentration-dependent manner. Thienorphine and buprenorphine concentration-dependently decreased the AUC of isolated choledochus, while morphine increased the AUC of isolated choledochus. Thienorphine had no effect on the contractile amplitude or basal tension of isolated gall bladder muscle strips. In contrast, buprenorphine and morphine increased the contractile basal tension of isolated gall bladder muscle strips in a concentration-dependent manner. Thienorphine (0.01-1.0mg/kg) had no significant inhibitory effect on bile flow. However, morphine (1.0-10mg/kg) and buprenorphine (1.0mg/kg) significantly inhibited bile flow. The maximum inhibition of bile flow by buprenorphine was 63.9±12.9% and by morphine was 74.1±11.3%. In summary, thienorphine has little influence on the guinea pig isolated sphincter of Oddi, choledochus and gall bladder or on bile flow, which may result in a lack of adverse biliary colic effects.