Interaction between Mu and Delta Opioid Receptor Agonists in an Assay of Capsaicin-Induced Thermal Allodynia in Rhesus Monkeys

Delta opioid agonists enhance antinociceptive effects of mu-opioid agonists in many preclinical assays of acute nociception, but delta/mu interactions in preclinical models of inflammation-associated pain have not been examined. This study examined interactions between the delta agonist SNC80 [(+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] and the mu agonist analgesics methadone, morphine, and nalbuphine in an assay of capsaicin-induced thermal allodynia in rhesus monkeys. Thermal allodynia was produced by topical application of capsaicin to the tail. Antiallodynic effects of methadone, morphine, and nalbuphine were evaluated alone or in combination with fixed proportions of SNC80 identical to proportions previously shown to enhance acute thermal antinociceptive effects of these mu agonists in rhesus monkeys (0.9 : 1 SNC80/methadone; 0.29 : 1 SNC80/morphine; 3.6 : 1 SNC80/nalbuphine). Methadone, morphine, and nalbuphine each produced dose-dependent antiallodynia. SNC80 produced partial antiallodynia up to the highest dose tested (5.6 mg/kg). SNC80 produced a modest, enantioselective, and naltrindole-reversible enhancement of methadone-induced antiallodynia. However, SNC80 did not enhance morphine antiallodynia and only weakly enhanced nalbuphine antiallodynia. Overall, SNC80 produced modest or no enhancement of the antiallodynic effects of the three mu agonists evaluated. These results suggest that delta agonist-induced enhancement of mu agonist antiallodynia may be weaker and less reliable than previously demonstrated enhancement of mu agonist acute thermal nociception

Behavioral Evaluation of Modafinil and The Abuse-related Effects of Cocaine in Rhesus Monkeys

This article may not exactly replicate the final version published in the APA journal. It is not the copy of record.Modafinil is a central nervous system stimulant used to promote wakefulness, and it is being evaluated clinically as an agonist-based medication to treat stimulant abuse. This is the first report of the effects of modafinil on the abuse-related effects of cocaine in nonhuman primates. Three studies were conducted to examine the behavioral effects of modafinil. In the first study, the discriminative stimulus effects of modafinil were evaluated in monkeys trained to discriminate either low (0.18 mg/kg, IM) or high (0.4 mg/kg, IM) doses of cocaine from saline. Modafinil dose-dependently substituted for cocaine in 6/7 monkeys. In the second study, the effects of chronically administered modafinil (32-56 mg/kg/day, IV) on food- and cocaine-maintained operant responding were examined. Modafinil was administered 3 times/hr for 23 hr/day to ensure stable drug levels. Chronic treatment with 32 mg/kg/day modafinil selectively reduced responding maintained by intermediate (0.003 mg/kg/inj) and peak (0.01 mg/kg/inj) reinforcing doses of cocaine, but responding maintained by higher doses of cocaine was unaffected. Food-maintained behavior did not change during chronic treatment with modafinil. In a third study, after extinction of cocaine self-administration, modafinil (32 and 56 mg/kg/day, IV) significantly increased saline self-administration on the first day of treatment. These findings indicate that modafinil shares discriminative stimulus effects with cocaine and selectively reduces responding maintained by reinforcing doses of cocaine. These data are generally consistent with clinical findings and provide new evidence that these preclinical models may be useful for predicting the effectiveness of novel medications for drug abuse treatment

MDAN-21: A Bivalent Opioid Ligand Containing mu-Agonist and Delta-Antagonist Pharmacophores and Its Effects in Rhesus Monkeys

MDAN-21, , a bivalent opioid ligand containing a mu-opioid receptor agonist (derived from oxymorphone) linked to the delta-opioid receptor antagonist (related to naltrindole) by a spacer of 21 atoms, was reported to have potent analgesic properties in mice. Tolerance, physical dependence, and conditioned place preference were not evident in that species. The finding that bivalent ligands in this series, with spacers 19 atoms or greater, were devoid of tolerance and dependence led to the proposal that MDAN-21 targets heteromeric mu-delta-opioid receptors. The present study focused on its effects in nonhuman primates (Macaca mulatta), a species with a physiology and behavioral repertoire not unlike humans. With regard to opioids, this species usually better predicts clinical outcomes. MDAN-21 substituted for morphine in morphine-dependent monkeys in the remarkably low dose range 0.006–0.032 mg/kg, subcutaneously. Although MDAN-21 failed to produce reliable thermal analgesia in the dose range 0.0032–0.032 mg/kg, intramuscularly, it was active in the same dose range and by the same route of administration, in the capsaicin-induced thermal allodynia assay. The results suggest that MDAN-21 may be useful in the treatment of opioid dependence and allodynia. The data provide additional evidence that opioid withdrawal is associated with sensitized pain

Sustained pain-related depression of behavior: effects of intraplantar formalin and complete freund’s adjuvant on intracranial self-stimulation (ICSS) and endogenous kappa opioid biomarkers in rats

Background: Intraplantar administration of complete Freund's adjuvant (CFA) and formalin are two noxious stimuli commonly used to produce sustained pain-related behaviors in rodents for research on neurobiology and treatment of pain. One clinically relevant manifestation of pain is depression of behavior and mood. This study compared effects of intraplantar CFA and formalin on depression of positively reinforced operant behavior in an assay of intracranial self-stimulation (ICSS) in rats. Effects of CFA and formalin on other physiological and behavioral measures, and opioid effects on formalin-induced depression of ICSS, were also examined. Results: There were four main findings. First, consistent with previous studies, both CFA and formalin produced similar paw swelling and mechanical hypersensitivity. Second, CFA produced weak and transient depression of ICSS, whereas formalin produced a more robust and sustained depression of ICSS that lasted at least 14 days. Third, formalin-induced depression of ICSS was reversed by morphine doses that did not significantly alter ICSS in saline-treated rats, suggesting that formalin effects on ICSS can be interpreted as an example of pain-related and analgesic-reversible depression of behavior. Finally, formalin-induced depression of ICSS was not associated with changes in central biomarkers for activation of endogenous kappa opioid systems, which have been implicated in depressive-like states in rodents, nor was it blocked by the kappa antagonist norbinaltorphimine. Conclusions: These results suggest differential efficacy of sustained pain stimuli to depress brain reward function in rats as assessed with ICSS. Formalin-induced depression of ICSS does not appear to engage brain kappa opioid systems. Electronic supplementary material The online version of this article (doi:10.1186/1744-8069-10-62) contains supplementary material, which is available to authorized users

Climbing behavior by mice as an endpoint for preclinical assessment of drug effects in the absence and presence of pain

This study evaluated climbing in mice as a tool to assess the expression and treatment of pain-related behavioral depression in male and female ICR mice. Mice were videotaped during 10-min sessions in a vertical plexiglass cylinder with wire mesh walls, and “Time Climbing” was scored by observers blind to treatments. Initial validation studies demonstrated that baseline climbing was stable across repeated days of testing and depressed by intraperitoneal injection of dilute lactic acid (IP acid) as an acute pain stimulus. Additionally, IP acid-induced depression of climbing was blocked by the positive-control non-steroidal anti-inflammatory drug (NSAID) ketoprofen but not by the negative control kappa opioid receptor agonist U69593. Subsequent studies examined effects of single-molecule opioids (fentanyl, buprenorphine, naltrexone) and of fixed-proportion fentanyl/naltrexone mixtures (10:1, 3.2:1, and 1:1) that vary in their efficacy at the mu opioid receptor (MOR). Opioids administered alone produced a dose- and efficacy-dependent decrease in climbing, and fentanyl/naltrexone-mixture data indicated that climbing in mice is especially sensitive to disruption by even low-efficacy MOR activation. Opioids administered as a pretreatment to IP acid failed to block IP acid-induced depression of climbing. Taken together, these findings support the utility of climbing in mice as an endpoint to evaluate candidate-analgesic effectiveness both to (a) produce undesirable behavioral disruption when the test drug is administered alone, and (b) produce a therapeutic blockade of pain-related behavioral depression. The failure of MOR agonists to block IP acid-induced depression of climbing likely reflects the high sensitivity of climbing to disruption by MOR agonists

Rat Nucleus Accumbens Core Astrocytes Modulate Reward and the Motivation to Self-Administer Ethanol after Abstinence

Our understanding of the active role that astrocytes play in modulating neuronal function and behavior is rapidly expanding, but little is known about the role that astrocytes may play in drug-seeking behavior for commonly abused substances. Given that the nucleus accumbens is critically involved in substance abuse and motivation, we sought to determine whether nucleus accumbens astrocytes influence the motivation to self-administer ethanol following abstinence. We found that the packing density of astrocytes that were expressing glial fibrillary acidic protein increased in the nucleus accumbens core (NAcore) during abstinence from EtOH self-administration. No change was observed in the nucleus accumbens shell. This increased NAcore astrocyte density positively correlated with the motivation for ethanol. Astrocytes can communicate with one another and influence neuronal activity through gap-junction hemichannels. Because of this, the effect of blocking gap-junction hemichannels on the motivation for ethanol was examined. The motivation to self-administer ethanol after 3 weeks abstinence was increased following microinjection of gap-junction hemichannel blockers into the NAcore at doses that block both neuronal and astrocytic channels. In contrast, no effect was observed following microinjection of doses that are not thought to block astrocytic channels or following microinjection of either dose into the nucleus accumbens shell. Additionally, the motivation for sucrose after 3 weeks abstinence was unaffected by NAcore gap-junction hemichannel blockers. Next, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were selectively expressed in NAcore astrocytes to test the effect of astrocyte stimulation. DREADD activation increased cytosolic calcium in primary astrocytes, facilitated responding for rewarding brain stimulation, and reduced the motivation for ethanol after 3 weeks abstinence. This is the first work to modulate drug-seeking behavior with astrocyte-specific DREADDs. Taken together, our findings demonstrate that NAcore astrocytes can shape the motivation to self-administer ethanol; suggesting that the development of ligands which selectively stimulate astrocytes may be a successful strategy to abate ethanol-seeking behavior

Differential effects of systemically administered nor-binaltorphimine (nor-BNI) on κ-opioid agonists in the mouse writhing assay

The opioid antagonist effects of systemically administered nor-binaltorphimine (nor-BNI) were evaluated against the kappa agonists CI-977, U69,593, U50,488, ethylketocyclazocine (EKC), Mr2034 and bremazocine, the mu agonist morphine and the alkaloid delta agonist BW-373U86 in the acetic acid-induced writhing assay in mice. All eight agonists completely and dose-dependently inhibited writhing. Antagonism of CI-977 was apparent 1 h after administration of 32 mg/kg nor-BNI, peaking after 4 h and was maintained for at least 4 weeks; no antagonist effects of nor-BNI were apparent after 8 weeks. Nor-BNI (32 mg/kg) caused little or no antagonism of morphine or BW-373U86 at 1 h and none at 24 h after nor-BNI administration. Subsequently, dose-effect curves for CI-977, U50,488, U69,593, EKC, Mr2034 and bremazocine were determined 24 h after pretreatment with 3.2, 10 and 32 mg/kg nor-BNI. Pretreatment with 3.2 mg/kg nor-BNI produced significant antagonism of all six kappa agonists, suggesting that their antinociceptive effects were mediated at least in part by nor-BNI-sensitive kappa receptors. At higher doses, nor-BNI dose-depend-ently shifted the agonist dose-effect curves of CI-977, U50,488, U69,593 and bremazocine, but not those of EKC and Mr2034, suggesting that the latter compounds may be producing effects via nor-BNI-insensitive receptors. Mu receptor involvement was demonstrated following a 24 h pretreatment with 32 mg/kg β -FNA in combination with nor-BNI, which significantly increased the degree of antagonism of Mr2034 and EKC from that seen with nor-BNI alone. Hence, SC administered nor-BNI selectively antagonized agonist activity mediated through kappaopioid receptors without differentiating between kappa subtypes. Nor-BNI also enabled the mu agonist activity of proposed kappa agonists to be measured.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46343/1/213_2005_Article_BF02245071.pd

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR

Relationship of edge localized mode burst times with divertor flux loop signal phase in JET

A phase relationship is identified between sequential edge localized modes (ELMs) occurrence times in a set of H-mode tokamak plasmas to the voltage measured in full flux azimuthal loops in the divertor region. We focus on plasmas in the Joint European Torus where a steady H-mode is sustained over several seconds, during which ELMs are observed in the Be II emission at the divertor. The ELMs analysed arise from intrinsic ELMing, in that there is no deliberate intent to control the ELMing process by external means. We use ELM timings derived from the Be II signal to perform direct time domain analysis of the full flux loop VLD2 and VLD3 signals, which provide a high cadence global measurement proportional to the voltage induced by changes in poloidal magnetic flux. Specifically, we examine how the time interval between pairs of successive ELMs is linked to the time-evolving phase of the full flux loop signals. Each ELM produces a clear early pulse in the full flux loop signals, whose peak time is used to condition our analysis. The arrival time of the following ELM, relative to this pulse, is found to fall into one of two categories: (i) prompt ELMs, which are directly paced by the initial response seen in the flux loop signals; and (ii) all other ELMs, which occur after the initial response of the full flux loop signals has decayed in amplitude. The times at which ELMs in category (ii) occur, relative to the first ELM of the pair, are clustered at times when the instantaneous phase of the full flux loop signal is close to its value at the time of the first ELM