Pharmacological characterization and therapeutic potential for the treatment of opioid abuse with ATPM-ET, an N-ethyl substituted aminothiazolomorphinan with κ agonist and µ agonist/antagonist activity.

We previously reported that the κ agonists with mixed µ activity could attenuate heroin self-administration with less potential to develop tolerance. The present study further investigated the effects of (-)-3-N-Ethylamino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride (ATPM-ET), a κ agonist and µ agonist/antagonist, on the acquisition and reinstatement of morphine-induced conditioned place preference (CPP), heroin self-administration and heroin-primed reinstatement of drug-seeking behavior. We found that ATPM-ET produced a longer duration of potent antinociceptive effects with less side effect of sedation. More importantly, ATPM-ET attenuated the acquisition of morphine-induced CPP, without affecting the reinstatement of morphine CPP. Furthermore, ATPM-ET significantly inhibited heroin self-administration and the reinstatement of heroin primed drug-seeking behavior. Taken together, ATPM-ET, a novel κ agonist and µ agonist/antagonist may have utility for the treatment of drug dependence.

[Spatial distribution of sulfur dioxide around a tobacco bulk-curing workshop cluster].

In order to manifest lower energy consumption and less labor employment, and provide the theoretical basis for constructing environmentally friendly modem tobacco agriculture, this paper analyzed gas composition of the chimney from a bulk-curing barn and the dispersion of sulfur dioxide (SO2) around the workshop cluster using ecom-J2KN flue gas analyzer and air sampler. During curing, the concentrations of carbon dioxide (CO2) and SO2 in the chimney were both highest at 38 degrees C, while the concentration of nitrogen oxides (NOx) was highest at 42 degrees C. The emission concentration of SO2 from the chimney was 1327.60-2218.40 mg x m(-3). Average SO2 emission would decrease by 49.7% through adding 4.0% of a sulfur-fixed agent. The highest concentrations of SO2 in the surface soil appeared at the yellowing stage. SO2 concentration in horizontal direction localized at 43-80 m exceeded 0.5 mg x m(-3). The highest concentration of SO2 (0.57 mg x m(-3)) was observed at 50 m. At 50 m in the downstream wind direction of the workshop cluster, SO2 concentration in vertical direction localized at 0.9-1.8 m exceeded 0.5 mg x m(-3), and the highest concentration of SO2 in vertical direction was 0.65 mg x m(-3) at 1.6 m. During curing, the average concentration of SO2 was decreased by 0.43 mg x m(-3) by using the sulfur-fixed agent. The polluted boundary was localized at 120 m in the downstream wind direction of the workshop cluster.

[Minimally invasive treatment of intertrochanteric fractures with locking compression plate in the elderly].

OBJECTIVE: To study the effect of minimally invasive treatment with the locking compression plate (LCP) in the treatment of intertrochanteric fractures in the elderly age. METHODS: 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). RESULTS: 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. CONCLUSION: Minimally invasive approaches with LCP could treat the elder intertrochanteric fractures with the advantages such as minimal invasive, stable fixation and less blood loss.

Adenosine A(1) receptor agonist N(6)-cyclohexyl-adenosine induced phosphorylation of delta opioid receptor and desensitization of its signaling.

AIM: To define the effect of adenosine A(1) receptor (A(1)R) on delta opioid receptor (DOR)-mediated signal transduction. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Chronic morphine treatment impaired hippocampal long-term potentiation and spatial memory via accumulation of extracellular adenosine acting on adenosine A1 receptors.

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.

Paradoxical relationship between RAVE (relative activity versus endocytosis) values of several opioid receptor agonists and their liability to cause dependence.

AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.