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Jian-feng SUN,
Yu-hua WANG,
Fu-ying LI,
Gang LU,
Yi-min TAO,
Yun CHENG,
Jie CHEN,
Xue-jun XU,
Zhi-qiang CHI,
John L NEUMEYER,
Ao ZHANG,
Jing-gen LIU
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ABSTRACT: to investigate the effects of ATPM-ET [(-)-3-N-Ethylaminothiazolo [5,4-b]-N-cyclopropylmethylmorphinan hydrochloride] on physical dependence and behavioral sensitization to morphine in mice.
the pharmacological profile of ATPM-ET was characterized using competitive binding and GTPγS binding assays. We then examined the antinociceptive effects of ATPM-ET in the hot plate test. Morphine dependence assay and behavioral sensitization assay were used to determine the effect of ATPM-ET on physical dependence and behavior sensitization to morphine in mice.
the binding assay indicated that ATPM-ET ATPM-ET exhibited a high affinity to both κ- and μ-opioid receptors with K(i) values of 0.15 nmol/L and 4.7 nmol/L, respectively, indicating it was a full κ-opioid receptor agonist and a partial μ-opioid receptor agonist. In the hot plate test, ATPM-ET produced a dose-dependent antinociceptive effect, with an ED(50) value of 2.68 (2.34-3.07) mg/kg. Administration of ATPM-ET (1 and 2 mg/kg, sc) prior to naloxone (3.0 mg/kg, sc) injection significantly inhibited withdrawal jumping of mice. In addition, ATPM-ET (1 and 2 mg/kg, sc) also showed a trend toward decreasing morphine withdrawal-induced weight loss. ATPM-ET (1.5 and 3 mg/kg, sc) 15 min before the morphine challenge significantly inhibited the morphine-induced behavior sensitization (P<0.05).
ATPM-ET may have potential as a therapeutic agent for the treatment of drug abuse.
Acta Pharmacologica Sinica 12/2010; 31(12):1547-52. · 1.95 Impact Factor
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Jian-feng Sun,
Yu-hua Wang,
Fu-ying Li,
Gang Lu,
Yi-min Tao,
Yun Cheng,
Jie Chen,
Xue-jun Xu,
Zhi-qiang Chi,
John L Neumeyer,
Ao Zhang,
Jing-gen Liu
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ABSTRACT: Aim: To investigate the effects of ATPM-ET [(−)-3-N-Ethylaminothiazolo [5,4-b]-N-cyclopropylmethylmorphinan hydrochloride] on physical dependence and behavioral sensitization to morphine in mice.
Acta Pharmacologica Sinica 11/2010; 31(12):1547-1552. · 1.95 Impact Factor
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ABSTRACT: The kappa-opioid receptor (KOR), a member of the opioid receptor family, is widely expressed in the central nervous system and peripheral tissues. Substantial evidence has shown that activation of KOR by agonists and endogenous opioid peptides in vivo may produce a strong analgesic effect that is free from the abuse potential and the adverse side effects of mu-opioid receptor (MOR) agonists, such as morphine. In addition, activation of the KOR has also been shown to exert an inverse effect on morphine-induced adverse actions, such as tolerance, reward, and impairment of learning and memory. Therefore, the KOR has received much attention in the effort to develop alternative analgesics to MOR agonists and agents for the treatment of drug addiction. However, KOR agonists also produce several severe undesirable side effects such as dysphoria, water diuresis, salivation, emesis, and sedation in nonhuman primates, which may limit the clinical utility of KOR agonists for pain and drug abuse treatment. This article will review the role of KOR activation in mediating antinociception and addiction. The possible therapeutic application of kappa-agonists in the treatment of pain and drug addiction is also discussed.
Acta Pharmacologica Sinica 09/2010; 31(9):1065-70. · 1.95 Impact Factor
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ABSTRACT: The κ-opioid receptor (KOR), a member of the opioid receptor family, is widely expressed in the central nervous system and peripheral tissues. Substantial evidence has shown that activation of KOR by agonists and endogenous opioid peptides in vivo may produce a strong analgesic effect that is free from the abuse potential and the adverse side effects of μ-opioid receptor (MOR) agonists, such as morphine. In addition, activation of the KOR has also been shown to exert an inverse effect on morphine-induced adverse actions, such as tolerance, reward, and impairment of learning and memory. Therefore, the KOR has received much attention in the effort to develop alternative analgesics to MOR agonists and agents for the treatment of drug addiction. However, KOR agonists also produce several severe undesirable side effects such as dysphoria, water diuresis, salivation, emesis, and sedation in nonhuman primates, which may limit the clinical utility of KOR agonists for pain and drug abuse treatment. This article will review the role of KOR activation in mediating antinociception and addiction. The possible therapeutic application of κ-agonists in the treatment of pain and drug addiction is also discussed.Keywords: κ-opioid receptor; dynorphin; desensitization; antinociception; tolerance; addiction; drug withdrawal; cocaine reward; negative mood state
Acta Pharmacologica Sinica 08/2010; 31(9):1065-1070. · 1.95 Impact Factor
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ABSTRACT: To define the effect of adenosine A(1) receptor (A(1)R) on delta opioid receptor (DOR)-mediated signal transduction.
CHO cells stably expressing HA-tagged A(1)R and DOR-CFP fusion protein were used. The localization of receptors was observed using confocal microscope. DOR-mediated inhibition of adenylyl cyclase was measured using cyclic AMP assay. Western blots were employed to detect the phosphorylation of Akt and the DOR. The effect of A(1)R agonist N(6)-cyclohexyladenosine (CHA) on DOR down-regulation was assessed using radioligand binding assay.
CHA 1 micromol/L time-dependently attenuated DOR agonist [D-Pen(2,5)]enkephalin (DPDPE)-induced inhibition of intracellular cAMP accumulation with a t(1/2)=2.56 (2.09-3.31) h. Pretreatment with 1 micromol/L CHA for 24 h caused a right shift of the dose-response curve of DPDPE-mediated inhibition of cAMP accumulation, with a significant increase in EC(50) but no change in E(max). Pretreatment with 1 micromol/L CHA for 1 h also induced a significant attenuation of DPDPE-stimulated phosphorylation of Akt. Moreover, CHA time-dependently phosphorylated DOR (Ser363), and this effect was inhibited by A(1)R antagonist 1,3-Dipropyl-8-cyclopentylxanthine (DPCPX) but not by DOR antagonist naloxone. However, CHA failed to produce the down-regulation of DOR, as neither receptor affinity (K(d)) nor receptor density (B(max)) of DOR showed significant change after chronic CHA exposure.
Activation of A(1)R by its agonist caused heterologous desensitization of DOR-mediated inhibition of intracellular cAMP accumulation and phosphorylation of Akt. Activation of A(1)R by its agonist also induced heterologous phosphorylation but not down-regulation of DOR.
Acta Pharmacologica Sinica 07/2010; 31(7):784-90. · 1.95 Impact Factor
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ABSTRACT: Aim: To define the effect of adenosine A1 receptor (A1R) on delta opioid receptor (DOR)-mediated signal transduction.
Acta Pharmacologica Sinica 06/2010; 31(7):784-790. · 1.95 Impact Factor
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ABSTRACT: To study the effect of minimally invasive treatment with the locking compression plate (LCP) in the treatment of intertrochanteric fractures in the elderly age.
Twenty-eight cases of intertrochanteric fracture were retrospective studied from August 2007 to January 2009, included 13 males and 15 females with an average age of 78.6 years ranging from 70 to 102 years. All the 28 patients were treated with minimally invasive operations with locking compression plates. The time from injury to operation was ranged from 3 to 8 days (with an average of 4.5 days).
The operation time was from 40 to 90 minutes (with an average of 55 minutes). The average bleeding volume during the operation was 70 ml (from 50 to 150 ml). One patient died during hospital stay. Twenty-five patients were followed up from 6 months to 2 years with an average of 15 months after operation. The fracture healing time was from 10 to 12 weeks (10.4 weeks in average). According to an evaluation standard of HUANG Gong-yi, the results were excellent in 20 cases,good in 4 cases, poor in 1 case.
Minimally invasive approaches with LCP could treat the elder intertrochanteric fractures with the advantages such as minimal invasive, stable fixation and less blood loss.
Zhongguo gu shang = China journal of orthopaedics and traumatology 05/2010; 23(5):337-9.
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Gang Lu,
Qi-Xin Zhou,
Shuo Kang,
Qing-Lin Li,
Liang-Cai Zhao,
Jia-Dong Chen, Jian-Feng Sun,
Jun Cao,
Yu-Jun Wang,
Jie Chen,
Xiao-Yan Chen,
Da-Fang Zhong,
Zhi-Qiang Chi,
Lin Xu,
Jing-Gen Liu
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ABSTRACT: Chronic exposure to opiates impairs hippocampal long-term potentiation (LTP) and spatial memory, but the underlying mechanisms remain to be elucidated. Given the well known effects of adenosine, an important neuromodulator, on hippocampal neuronal excitability and synaptic plasticity, we investigated the potential effect of changes in adenosine concentrations on chronic morphine treatment-induced impairment of hippocampal CA1 LTP and spatial memory. We found that chronic treatment in mice with either increasing doses (20-100 mg/kg) of morphine for 7 d or equal daily dose (20 mg/kg) of morphine for 12 d led to a significant increase of hippocampal extracellular adenosine concentrations. Importantly, we found that accumulated adenosine contributed to the inhibition of the hippocampal CA1 LTP and impairment of spatial memory retrieval measured in the Morris water maze. Adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine significantly reversed chronic morphine-induced impairment of hippocampal CA1 LTP and spatial memory. Likewise, adenosine deaminase, which converts adenosine into the inactive metabolite inosine, restored impaired hippocampal CA1 LTP. We further found that adenosine accumulation was attributable to the alteration of adenosine uptake but not adenosine metabolisms. Bidirectional nucleoside transporters (ENT2) appeared to play a key role in the reduction of adenosine uptake. Changes in PKC-alpha/beta activity were correlated with the attenuation of the ENT2 function in the short-term (2 h) but not in the long-term (7 d) period after the termination of morphine treatment. This study reveals a potential mechanism by which chronic exposure to morphine leads to impairment of both hippocampal LTP and spatial memory.
Journal of Neuroscience 04/2010; 30(14):5058-70. · 7.11 Impact Factor
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ABSTRACT: To examine the relationship between the RAVE (relative activity versus endocytosis) values of opiate agonists and their dependence liability by studying several potent analgesics with special profiles in the development of physical and psychological dependence.
The effects of (-)-cis-(3R,4S,2'R) ohmefentanyl (F9202), (+)-cis-(3R,4S,2'S) ohmefentanyl (F9204), dihydroetorphine (DHE) and morphine on [(35)S]GTP gamma S binding, forskolin-stimulated cAMP accumulation, and receptor internalization were studied in CHO cells stably expressing HA-tagged mu-opioid receptors (CHO-HA-MOR). cAMP overshoot in response to the withdrawal of these compound treatments was also tested.
All four agonists exhibited the same rank order of activity in stimulation of [(35)S]GTP gamma S binding, inhibition of adenylyl cyclase (AC) and induction of receptor internalization: DHE>F9204>F9202>morphine. Based on these findings and the previous in vivo analgesic data obtained from our and other laboratories, the RAVE values of the four agonists were calculated. The rank order of RAVE values was morphine>F9202>F9204>DHE. For the induction of cAMP overshoot, the rank order was F9202>or=morphine>F9204>or=DHE.
Taken in combination with previous findings of these compounds' liability to develop dependence, the present study suggests that the agonist with the highest RAVE value seems to have a relatively greater liability to develop psychological dependence relative to the agonist with the lowest RAVE value. However, the RAVE values of these agonists are not correlated with their probability of developing physical dependence or inducing cAMP overshoot, a cellular hallmark of dependence.
Acta Pharmacologica Sinica 03/2010; 31(4):393-8. · 1.95 Impact Factor
