Interactions between opioid agonists and glutamate receptor antagonists

The following studies systematically examine the interactive effects of opioids and glutamate receptor antagonists in assays of schedule-controlled responding and thermal nociception. Experiment 1 examines the effects of morphine, buprenorphine, butorphanol, and nalbuphine alone and in combination with an N-Methyl-D-Aspartate (NMDA) receptor antagonist on schedule-controlled responding and thermal nociception. The results from this study indicate that NMDA antagonist/morphine and NMDA antagonist/buprenorphine mixtures produce additive or infra-additive effects on schedule-controlled responding, whereas NMDA antagonist/butorphanol and NMDA antagonist/nalbuphine mixtures produced additive or supra-additive effects. In addition, mixtures of an NMDA antagonist in combination with morphine, buprenorphine, butorphanol, and nalbuphine produce additive or supra-additive effects on thermal nociception. Experiment 2 examines the interactive effects of morphine in combination with metabotropic glutamate (mGlu) receptor antagonists selective for mGlu1, mGlu5, and mGlu2/3 receptor subtypes on schedule-controlled responding and thermal nociception. The results from this experiment suggest that mGlu1, mGlu5, and mGlu2/3 antagonists produce additive effects when administered in combination with morphine on schedule-controlled iv responding. In contrast, mGlu1 and mGlu2/3 antagonists produced supra-additive effects with morphine when assessed on thermal nociception. Experiment 3 assesses the effects of NMDA, mGlu1, mGlu5, and mGlu2/3 receptor antagonists on the efficacy of buprenorphine and dezocine in an assay of thermal nociception. Under conditions in which buprenorphine and dezocine produce sub-maximal antinociceptive effects, these drugs are assessed after pretreatment with NMDA, mGlu1, mGlu5, and mGlu2/3 antagonists. The results from this study indicate that NMDA, mGlu1, and mGlu2/3 receptor antagonists increase the efficacy of both buprenorphine and dezocine on thermal nociception. Taken together, these experiments assessed the interactive effects of opioid receptor agonists and glutamate receptor antagonists on schedule-controlled responding and thermal nociception. The experimental results obtained from these studies suggest that these interactive effects are dependent upon factors such as the relative proportions of drugs and the experimental endpoint under study. In addition, the pharmacological affinity of the opioid and glutamate receptor antagonist being examined is an important determinant of their behavioral effects

Irritable Bowel Syndrome: Clinical Manifestations, Dietary Influences, and Management.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that is characterized by symptoms of chronic abdominal pain and altered bowel habits in the absence of an overtly identifiable cause. It is the most commonly diagnosed functional gastrointestinal disorder, accounting for about one third of gastroenterology visits. It generally presents as a complex of symptoms, including psychological dysfunction. Hypersensitivity to certain foods, especially foods that contain high amounts of fructose, plays a role in the pathophysiology of IBS. Elevated consumption of high-fructose corn syrup (HFCS) has been discussed in this aspect. The treatment options for IBS are challenging and varied. In addition to dietary restrictions for HFCS-induced IBS, such as low-FODMAP (Fermentable Oligosaccharides, Disaccharide, Monosaccharides, and Polyols) diets, existing drug therapies are administered based on the predominant symptoms and IBS-subtype. Patients with IBS are likely to suffer from issues, such as anxiety, depression, and post-traumatic-stress disorder. Biopsychosocial factors particularly socioeconomic status, sex, and race should, thus, be considered for diagnostic evaluation of patients with IBS

Animal models of rheumatoid pain: experimental systems and insights.

Severe chronic pain is one of the hallmarks and most debilitating manifestations of inflammatory arthritis. It represents a significant problem in the clinical management of patients with common chronic inflammatory joint conditions such as rheumatoid arthritis, psoriatic arthritis and spondyloarthropathies. The functional links between peripheral inflammatory signals and the establishment of the neuroadaptive mechanisms acting in nociceptors and in the central nervous system in the establishment of chronic and neuropathic pain are still poorly understood, representing an area of intense study and translational priority. Several well-established inducible and spontaneous animal models are available to study the onset, progression and chronicization of inflammatory joint disease, and have been instrumental in elucidating its immunopathogenesis. However, quantitative assessment of pain in animal models is technically and conceptually challenging, and it is only in recent years that inflammatory arthritis models have begun to be utilized systematically in experimental pain studies using behavioral and neurophysiological approaches to characterize acute and chronic pain stages. This article aims primarily to provide clinical and experimental rheumatologists with an overview of current animal models of arthritis pain, and to summarize emerging findings, challenges and unanswered questions in the field

Antagonism of triazolam self-administration in rhesus monkeys responding under a progressive-ratio schedule: In vivo apparent pA2 analysis.

BACKGROUND: Conventional benzodiazepines bind non-selectively to GABAA receptors containing α1, α2, α3, and α5 subunits (α1GABAA, α2GABAA, α3GABAA, and α5GABAA receptors, respectively), and the role of these different GABAA receptor subtypes in the reinforcing effects of benzodiazepines has not been characterized fully. We used a pharmacological antagonist approach with available subtype-selective ligands to evaluate the role of GABAA receptor subtypes in the reinforcing effects of the non-selective conventional benzodiazepine, triazolam. METHODS: Rhesus monkeys (n=4) were trained under a progressive-ratio schedule of intravenous midazolam delivery and dose-response functions were determined for triazolam, in the absence and presence of flumazenil (non-selective antagonist), βCCT and 3-PBC (α1GABAA-preferring antagonists), and XLi-093 (α5GABAA-selective antagonist). RESULTS: Flumazenil, βCCT and 3-PBC shifted the dose-response functions for triazolam to the right in a surmountable fashion, whereas XLi-093 was ineffective. Schild analyses revealed rank orders of potencies of flumazenil=βCCT\u3e3-PBC. Comparison of potencies between self-administration and previous binding studies with human cloned GABAA receptor subtypes suggested that the potencies for βCCT and 3-PBC were most consistent with binding at α2GABAA and α3GABAA receptors, but not α1GABAA or α5GABAA receptor subtypes. CONCLUSIONS: Our findings were not entirely consistent with blockade of α1GABAA receptors and are consistent with the possibility of α2GABAA and/or α3GABAA subtype involvement in antagonism of the reinforcing effects of triazolam. The α5GABAA receptor subtype likely does not play a substantial role in self-administration under these conditions

Role of gamma-aminobutyric acid type A (GABAA) receptor subtypes in acute benzodiazepine physical dependence-like effects: evidence from squirrel monkeys responding under a schedule of food presentation.

RATIONALE: Assays of schedule-controlled responding can be used to characterize the pharmacology of benzodiazepines and other GABAA receptor modulators, and are sensitive to changes in drug effects that are related to physical dependence. OBJECTIVE: The present study used this approach to investigate the role of GABAA receptor subtypes in mediating dependence-like effects following benzodiazepine administration. METHODS: Squirrel monkeys (n = 6) were trained on a fixed-ratio schedule of food reinforcement. Initially, the response rate-decreasing effects of chlordiazepoxide (0.1-10 mg/kg; nonselective GABAA receptor agonist), zolpidem (0.032-1.0 mg/kg; α1 subunit-containing GABAA subtype-preferring agonist), and HZ-166 (0.1-10 mg/kg; functionally selective α2 and α3 subunit-containing GABAA receptor agonist) were assessed. Next, acute dependence-like effects following single injections of chlordiazepoxide, zolpidem, and HZ-166 were assessed with flumazenil (0.1-3.2 mg/kg; nonselective GABAA receptor antagonist). Finally, acute dependence-like effects following zolpidem administration were assessed with βCCt and 3-PBC (0.1-3.2 mg/kg and 0.32-10 mg/kg, respectively; α1 subunit-containing GABAA receptor antagonists). RESULTS: Chlordiazepoxide, zolpidem, and HZ-166 produced dose- and time-dependent decreases in response rates, whereas flumazenil, βCCT, and 3-PBC were ineffective. After the drug effects waned, flumazenil produced dose-dependent decreases in response rates following administration of 10 mg/kg chlordiazepoxide and 1.0 mg/kg zolpidem, but not following any dose of HZ-166. Further, both βCCT and 3-PBC produced dose-dependent decreases in response rates when administered after 1.0 mg/kg zolpidem. CONCLUSIONS: These data raise the possibility that α1 subunit-containing GABAA receptors play a major role in physical dependence-related behaviors following a single injection of a benzodiazepine

Attenuation of morphine antinociceptive tolerance by a CB1 receptor agonist and an NMDA receptor antagonist: Interactive effects

CB1 cannabinoid (CB1) receptor agonists and N-Methyl-d-Aspartate (NMDA) receptor antagonists attenuate the development of morphine antinociceptive tolerance. The present study used dose-addition analysis to evaluate CB1/NMDA receptor interactions on this endpoint. Chronic morphine administration (5 days, 100 mg/kg, twice daily) resulted in a 2.8-fold rightward shift in the morphine dose-effect curve. Co-administration of either the CB1 receptor agonist CP-55940 (5-(1,1-Dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol; 0.32-1.0 mg/kg) or the NMDA receptor antagonist (−)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959; 1.0-3.2 mg/kg) with morphine dose-dependently attenuated morphine tolerance. The relative potency of each drug alone was quantified using a defined level of effect (one-quarter log shift in the morphine dose-effect curve), resulting in equieffective doses of 0.42 mg/kg and 1.1 mg/kg for CP-55940 and LY235959, respectively. Subsequent experiments assessed CP-55940/LY235959 interactions using a fixed-proportion design. Co-administration of CP-55940/LY235959 mixtures (1:1, 1:3.2, or 1:10 CP-55940/LY235959) with morphine dose-dependently attenuated morphine tolerance. Isobolographic and dose-addition analysis were used to statistically compare the experimentally determined potency for each mixture (zmix) with predicted additive potency (zadd). Mixtures of 1:1 and 1:3.2 CP-55940/LY235959 produced additive effects (zadd = zmix), while the mixture of 1:10 CP-55940/LY235959 produced a supra-additive effect (zadd > zmix). These results suggest that CP-55940 and LY235959 produce additive or supra-additive attenuation of morphine antinociceptive tolerance after repeated morphine administration, depending on their relative concentrations

Observations of Arp 220 using Herschel-SPIRE: An Unprecedented View of the Molecular Gas in an Extreme Star Formation Environment

We present Herschel SPIRE-FTS observations of Arp~220, a nearby ULIRG. The FTS continuously covers 190 -- 670 microns, providing a good measurement of the continuum and detection of several molecular and atomic species. We detect luminous CO (J = 4-3 to 13-12) and water ladders with comparable total luminosity; very high-J HCN absorption; OH+, H2O+, and HF in absorption; and CI and NII. Modeling of the continuum yields warm dust, with T = 66 K, and an unusually large optical depth of ~5 at 100 microns. Non-LTE modeling of the CO shows two temperature components: cold molecular gas at T ~ 50 K and warm molecular gas at T ~1350 K. The mass of the warm gas is 10% of the cold gas, but dominates the luminosity of the CO ladder. The temperature of the warm gas is in excellent agreement with H2 rotational lines. At 1350 K, H2 dominates the cooling (~20 L_sun/M_sun) in the ISM compared to CO (~0.4 L_sun/M_sun). We found that only a non-ionizing source such as the mechanical energy from supernovae and stellar winds can excite the warm gas and satisfy the energy budget of ~20 L_sun/M_sun. We detect a massive molecular outflow in Arp 220 from the analysis of strong P-Cygni line profiles observed in OH+, H2O+, and H2O. The outflow has a mass > 10^{7} M_sun and is bound to the nuclei with velocity < 250 km/s. The large column densities observed for these molecular ions strongly favor the existence of an X-ray luminous AGN (10^{44} ergs/s) in Arp 220.Comment: Accepted in ApJ on September 1, 201

Opioid antinociception, tolerance and dependence: interactions with the N-methyl-D-aspartate system in mice

This study explored the involvement of N-methyl-D-aspartate (NMDA) in the effects of mu opioid agonists. A hot plate procedure was used to assess antinociception and tolerance in mice in which the NR1 subunit of the NMDA receptor was reduced (knocked down, KD) to approximately 10% and in mice treated with the NMDA antagonist, LY235959 [(−)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboylic acid]. The mu opioid agonists, morphine, l-methadone and fentanyl, were approximately 3-fold less potent in the NR1 KD mice than in wild type (WT) controls; however, the development of morphine tolerance and dependence did not differ markedly in the NR1 KD and WT mice. Acute administration of the NMDA antagonist, LY235959 produced dose-dependent, leftward shifts in the morphine dose-effect curve in WT mice, but not in the NR1 KD mice. Chronic administration of LY235959 during the morphine tolerance regimen did not attenuate the development of tolerance in the NR1 KD nor the WT mice. These results indicate that the NR1 subunit of the NMDA receptor does not play a prominent role in mu opioid tolerance

ISO Far-IR Spectroscopy of IR-Bright Galaxies and ULIRGs

Based on far-infrared spectroscopy of a small sample of nearby infrared-bright and ultraluminous infrared galaxies (ULIRGs) with the ISO Long Wavelength Spectrometer, we find a dramatic progression in ionic/atomic fine-structure emission line and molecular/atomic absorption line characteristics in these galaxies extending from strong [O III]52,88 and [N III]57 micron line emission to detection of only faint [C II]158 micron line emission from gas in photodissociation regions in the ULIRGs. The molecular absorption spectra show varying excitation as well, extending from galaxies in which the molecular population mainly occupies the ground state to galaxies in which there is significant population in higher levels. In the case of the prototypical ULIRG, the merger galaxy Arp 220, the spectrum is dominated by absorption lines of OH, H2O, CH, and [O I]. Low [O III]88 micron line flux relative to the integrated far-infrared flux correlates with low excitation and does not appear to be due to far-infrared extinction or to density effects. A progression toward soft radiation fields or very dusty HII regions may explain these effects