Yu-Jun Wang

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 A1 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-α/β 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.

Role of Src in ligand-specific regulation of δ-opioid receptor desensitization and internalization

The opioid receptors are a member of G protein‐coupled receptors that mediate physiological effects of endogenous opioid peptides and structurally distinct opioid alkaloids. Although it is well characterized that there is differential receptor desensitization and internalization properties following activation by distinct agonists, the underlying mechanisms remain elusive. We investigated the signaling events of δ‐opioid receptor (δOR) initiated by two ligands, DPDPE and TIPP. We found that although both ligands inhibited adenylyl cyclase (AC) and activated ERK1/2, only DPDPE induced desensitization and internalization of the δOR. We further found that DPDPE, instead of TIPP, could activate GRK2 by phosphorylating the non‐receptor tyrosine kinase Src and translocating it to membrane receptors. Activation of GRK2 led to the phosphorylation of serine residues in the C‐terminal tail, which facilitates β‐arrestin1/2 membrane translocation. Meanwhile, we also found that DPDPE promoted β‐arrestin1 dephosphorylation in a Src‐dependent manner. Thus, DPDPE appears to strengthen β‐arrestin function by dual regulations: promoting β‐arrestin recruitment and increasing β‐arrestin dephosphorylation at the plasma membrane in a Src‐dependent manner. All effects initiated by DPDPE could be abolished or suppressed by PP2, an inhibitor of Src. Morphine, which has been previously shown to be unable to desensitize or internalize δOR, also behaved as TIPP in failure to utilize Src to regulate δOR signaling. These findings point to the existence of agonist‐specific utilization of Src to regulate δOR signaling and reveal the molecular events by which Src modulates δOR responsiveness.

Pharmacological Characterization of ATPM [(-)-3-Aminothiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride], a Novel Mixed κ-Agonist and μ-Agonist/-Antagonist That Attenuates Morphine Antinociceptive Tolerance and Heroin Self-Administration Behavior

ATPM [(-)-3-amino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride] was found to have mixed κ- and μ-opioid activity and identified to act as a full κ-agonist and a partial μ-agonist by in vitro binding assays. The present study was undertaken to characterize its in vivo effects on morphine antinociceptive tolerance in mice and heroin self-administration in rats. ATPM was demonstrated to yield more potent antinociceptive effects than (-)U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide). It was further found that the antinociceptive effects of ATPM were mediated by κ- and μ-, but not δ-opioid, receptors. In addition to its agonist profile on the μ-receptor, ATPM also acted as a μ-antagonist, as measured by its inhibition of morphine-induced antinociception. It is more important that ATPM had a greater ratio of the ED50 value of sedation to that of antinociception than (-)U50,488 (11.8 versus 3.7), indicative of a less sedative effect than (-)U50,488H. In addition, ATPM showed less potential to develop antinociceptive tolerance relative to (-)U50,488H and morphine. Moreover, it dose-dependently inhibited morphine-induced antinociceptive tolerance. Furthermore, it was found that chronic treatment of rats for 8 consecutive days with ATPM (0.5 mg/kg s.c.) produced sustained decreases in heroin self-administration. (-)U50,488H (2 mg/kg s.c.) also produced similar inhibitory effect. Taken together, our findings demonstrated that ATPM, a novel mixed κ-agonist and μ-agonist/-antagonist, could inhibit morphine-induced antinociceptive tolerance, with less potential to develop tolerance and reduce heroin self-administration with less sedative effect. κ-Agonists with some μ-activity appear to offer some advantages over selective κ-agonists for the treatment of heroin abuse.

The role of the dynorphin/κ opioid receptor system in anxiety

Anxiety disorders are the most common and prevalent forms of psychiatric disease, although the biological basis of anxiety is not well understood. The dynorphin/κ opioid receptor system is widely distributed in the central nervous system and has been shown to play a critical role in modulating mood and emotional behaviors. In the present review, we summarize current literature relating to the role played by the dynorphin/κ opioid receptor system in anxiety and κ opioid receptor antagonists as potential therapeutic agents for the treatment of anxiety disorders.

Antagonism of κ opioid receptor in the nucleus accumbens prevents the depressive-like behaviors following prolonged morphine abstinence

The association between morphine withdrawal and depressive-like symptoms is well documented, however, the role of dynorphin/κ opioid receptor system and the underlying neural substrates have not been fully understood. In the present study, we found that four weeks morphine abstinence after a chronic escalating morphine regimen significantly induced depressive-like behaviors in mice. Prodynorphin mRNA and protein levels were increased in the nucleus accumbens (NAc) after four weeks of morphine withdrawal. Local injection of κ opioid receptor antagonist nor-Binaltorphimine (norBNI) in the NAc significantly blocked the expression of depressive-like behaviors without influencing general locomotor activity. Thus, the present study extends previous findings by showing that prolonged morphine withdrawal-induced depressive-like behaviors are regulated by dynorphin/κ opioid receptor system, and shed light on the κ opioid receptor antagonists as potential therapeutic agents for the treatment of depressive-like behaviors induced by opiate withdrawal.

Novel κ-opioid receptor agonist MB-1C-OH produces potent analgesia with less depression and sedation

Aim:To characterize the pharmacological profiles of a novel κ-opioid receptor agonist MB-1C-OH.Methods:[3H]diprenorphine binding and [35S]GTPγS binding assays were performed to determine the agonistic properties of MB-1C-OH. Hot plate, tail flick, acetic acid-induced writhing, and formalin tests were conducted in mice to evaluate the antinociceptive actions. Forced swimming and rotarod tests of mice were used to assess the sedation and depression actions.Results:In [3H]diprenorphine binding assay, MB-1C-OH did not bind to μ- and δ-opioid receptors at the concentration of 100 μmol/L, but showed a high affinity for κ-opioid receptor (Ki=35 nmol/L). In [35S]GTPγS binding assay, the compound had an Emax of 98% and an EC50 of 16.7 nmol/L for κ-opioid receptor. Subcutaneous injection of MB-1C-OH had no effects in both hot plate and tail flick tests, but produced potent antinociception in the acetic acid-induced writhing test (ED50=0.39 mg/kg), which was antagonized by pretreatment with a selective κ-opioid receptor antagonist Nor-BNI. In the formalin test, subcutaneous injection of MB-1C-OH did not affect the flinching behavior in the first phase, but significantly inhibited that in the second phase (ED50=0.87 mg/kg). In addition, the sedation or depression actions of MB-1C-OH were about 3-fold weaker than those of the classical κ agonist (−)U50,488H.Conclusion:MB-1C-OH is a novel κ-opioid receptor agonist that produces potent antinociception causing less sedation and depression.

Heteromers of μ opioid and dopamine D1 receptors modulate opioid-induced locomotor sensitization in a dopamine-independent manner

Exposure to opiates induces locomotor sensitization in rodents, which has been proposed to correspond to the compulsive drug‐seeking behaviour. Numerous studies have demonstrated that locomotor sensitization can occur in a dopamine transmission‐independent manner; however, the underlying mechanisms are unclear.

μ Opioid receptor-dopamine D1 receptor heteromers modulate opioid-induced locomotor sensitization in a dopamine-independent manner

Exposure to opiates induces locomotor sensitization in rodents, which has been proposed to correspond to the compulsive drug‐seeking behaviour. Numerous studies have demonstrated that locomotor sensitization can occur in a dopamine transmission‐independent manner; however, the underlying mechanisms are unclear.

The neuroprotective effect of memantine on methamphetamine-induced cognitive deficits

HIGHLIGHTSMETH impaired long term memory retention.METH changed expression levels of Bcl‐2 and cleaved caspase‐3 in the prefrontal cortex.MEM pretreatment improved METH‐induced cognitive function.MEM pretreatment reversed METH‐induced changes of protein levels of apoptotic‐related gene. ABSTRACT Repeated exposure to methamphetamine (METH) can cause severe neurotoxicity to the cortical neurons. In the present study, we investigated the effect of METH on cognitive function deficits, and determined the neuroprotective effects of memantine (MEM) on memory impairment induced by METH. The protein levels of Bcl‐2 and cleaved caspase‐3 in prefrontal cortex (PFC) were further examined to exploring the underlying mechanism. We found that repeated METH administration impaired long term (24 h) memory retention without affecting short term (5 min) memory retention. Co‐administration of MEM with METH before training session significantly improved METH‐induced cognitive function. METH significantly decreased expression level of Bcl‐2 and increased expression level of cleaved caspase‐3 in the PFC. The changes can be prevented by MEM pretreatment. Thus, these results demonstrated that MEM pretreatment reversed METH‐induced changes of protein levels of apoptotic‐related gene, and produced protective effects against METH‐induced cognitive deficits, suggesting the effectiveness of MEM may be due to its anti‐apoptotic activity.

Role for engagement of β-arrestin2 by the transactivated EGFR in agonist-specific regulation of δ receptor activation of ERK1/2

β‐Arrestins function as signal transducers linking GPCRs to ERK1/2 signalling either by scaffolding members of ERK1/2s cascades or by transactivating receptor tyrosine kinases through Src‐mediated release of transactivating factor. Recruitment of β‐arrestins to the activated GPCRs is required for ERK1/2 activation. Our previous studies showed that δ receptors activate ERK1/2 through a β‐arrestin‐dependent mechanism without inducing β‐arrestin binding to the δ receptors. However, the precise mechanisms involved remain to be established.