The blockade of the transient receptor potential vanilloid type 1 and fatty acid amide hydrolase decreases symptoms and central sequelae in the medial prefrontal cortex of neuropathic rats

<p>Abstract</p> <p>Background</p> <p>Neuropathic pain is a chronic disease resulting from dysfunction within the "pain matrix". The basolateral amygdala (BLA) can modulate cortical functions and interactions between this structure and the medial prefrontal cortex (mPFC) are important for integrating emotionally salient information. In this study, we have investigated the involvement of the transient receptor potential vanilloid type 1 (TRPV1) and the catabolic enzyme fatty acid amide hydrolase (FAAH) in the morphofunctional changes occurring in the pre-limbic/infra-limbic (PL/IL) cortex in neuropathic rats.</p> <p>Results</p> <p>The effect of <it>N</it>-arachidonoyl-serotonin (AA-5-HT), a hybrid FAAH inhibitor and TPRV1 channel antagonist, was tested on nociceptive behaviour associated with neuropathic pain as well as on some phenotypic changes occurring on PL/IL cortex pyramidal neurons. Those neurons were identified as belonging to the BLA-mPFC pathway by electrical stimulation of the BLA followed by hind-paw pressoceptive stimulus application. Changes in their spontaneous and evoked activity were studied in sham or spared nerve injury (SNI) rats before or after repeated treatment with AA-5-HT. Consistently with the SNI-induced changes in PL/IL cortex neurons which underwent profound phenotypic reorganization, suggesting a profound imbalance between excitatory and inhibitory responses in the mPFC neurons, we found an increase in extracellular glutamate levels, as well as the up-regulation of FAAH and TRPV1 in the PL/IL cortex of SNI rats. Daily treatment with AA-5-HT restored cortical neuronal activity, normalizing the electrophysiological changes associated with the peripheral injury of the sciatic nerve. Finally, a single acute intra-PL/IL cortex microinjection of AA-5-HT transiently decreased allodynia more effectively than URB597 or I-RTX, a selective FAAH inhibitor or a TRPV1 blocker, respectively.</p> <p>Conclusion</p> <p>These data suggest a possible involvement of endovanilloids in the cortical plastic changes associated with peripheral nerve injury and indicate that therapies able to normalize endovanilloid transmission may prove useful in ameliorating the symptoms and central sequelae associated with neuropathic pain.</p

The Third Fermi Large Area Telescope Catalog of Gamma-ray Pulsars

We present 294 pulsars found in GeV data from the Large Area Telescope (LAT) on the Fermi Gamma-ray Space Telescope. Another 33 millisecond pulsars (MSPs) discovered in deep radio searches of LAT sources will likely reveal pulsations once phase-connected rotation ephemerides are achieved. A further dozen optical and/or X-ray binary systems co-located with LAT sources also likely harbor gamma-ray MSPs. This catalog thus reports roughly 340 gamma-ray pulsars and candidates, 10% of all known pulsars, compared to $\leq 11$ known before Fermi. Half of the gamma-ray pulsars are young. Of these, the half that are undetected in radio have a broader Galactic latitude distribution than the young radio-loud pulsars. The others are MSPs, with 6 undetected in radio. Overall, >235 are bright enough above 50 MeV to fit the pulse profile, the energy spectrum, or both. For the common two-peaked profiles, the gamma-ray peak closest to the magnetic pole crossing generally has a softer spectrum. The spectral energy distributions tend to narrow as the spindown power $\dot E$ decreases to its observed minimum near $10^{33}$ erg s$^{-1}$, approaching the shape for synchrotron radiation from monoenergetic electrons. We calculate gamma-ray luminosities when distances are available. Our all-sky gamma-ray sensitivity map is useful for population syntheses. The electronic catalog version provides gamma-ray pulsar ephemerides, properties and fit results to guide and be compared with modeling results.Comment: 142 pages. Accepted by the Astrophysical Journal Supplemen

Supplement: "Localization and broadband follow-up of the gravitational-wave transient GW150914" (2016, ApJL, 826, L13)

This Supplement provides supporting material for Abbott et al. (2016a). We briefly summarize past electromagnetic (EM) follow-up efforts as well as the organization and policy of the current EM follow-up program. We compare the four probability sky maps produced for the gravitational-wave transient GW150914, and provide additional details of the EM follow-up observations that were performed in the different bands

N6/5’-DISUBSTITUTED ADENOSINE AND 2-CHLORO-ADENOSINE DERIVATIVES AS POTENT AND SELECTIVE A1 ADENOSINE RECEPTOR AGONISTS: SYNTHESIS, BINDING ASSAYS AND ANTINOCICEPTIVE ACTIVITY IN MICE

The A1 adenosine receptor (A1AR) is the best-characterized subtype of the four known adenosine receptors (ARs). Selective A1AR agonists mediate antiarrhythmic, antinociceptive and neuro- and cardioprotective effects. Moreover, A1AR agonists reduce lipolysis in adipose tissue. The A1AR is abundantly expressed in spinal cord and other neuronal tissue and its activation produced pain-relieving effects in a number of preclinical animal models [Gao Z-G and Jacobson KA, Expert Opin Emerg Drugs 2011, 16, 597]. Even though several selective A1AR agonists are being developed as analgesic, e.g. SDZ WAG 994, GR79236, GW-493838, it seems that all of them have been withdrawn possibly due to cardiovascular side effects. As A1AR is abundant in a number of tissues including CNS, heart and adipose tissues, A1AR full agonists can lead to severe cardiovascular side effects such as hypotension and bradycardia, limiting their clinical usefulness. Thus recent efforts have focused on developing ligands that will partially stimulate the A1AR [Cappellacci L et al., Bioorg. Med. Chem. 2008, 16, 336] or which are selective for certain signalling pathways (i.e. biased agonists). In our continuously efforts in searching potent and selective A1AR agonists, we have identified 5’-chloro-5’-deoxy-N6-(±)-(endo-norborn-2-yl)-adenosine (5’Cl5'd-(±)-ENBA) as a potent and highly selective full agonist of human A1AR (hA1AR (Ki) = 0.51 nM, A3/A1 = 2530) [Franchetti P et al., J. Med. Chem. 2009, 52, 2393]. Moreover, 5’Cl5’d-(±)-ENBA showed acute nocifensive effect in the formalin test and anti-neuropathic properties in a model of neuropathic pain, the spared nerve injury (SNI) of the sciatic nerve in mice. Interestingly, 5’Cl5’d-(±)-ENBA did not modify motor coordination and blood pressure or heart rate in unanaesthetized sham and SNI mice [Luongo L et al., Molecules 2012, 17, 13712]. The interesting biological properties of 5’Cl5’d-(±)-ENBA demonstrated that the substitution of 5’-hydroxyl group in adenosine analogues with a chlorine is well tolerated by A1AR and 5'-modified adenosine derivatives could be more druggable than 5'-unmodified ones, since normal ribonucleosides may be phosphorylated by adenosine kinases and then by nucleotide kinases to 5'-mono-, 5'-di-, or 5'-triphosphates and subsequently interact with P2Y receptors and/or other biological targets. As a proof of the concept, N6/5’-disubstituted adenosine and 2-chloro-adenosine derivatives were synthesized and evaluated for affinity and selectivity at all human adenosine receptor subtypes. Moreover, antinociceptive activity in a formalin test in mice was assayed. The results of these studies will be discussed

Role of metabotropic glutamate receptor 1 in the basolateral amygdala-driven prefrontal cortical deactivation in inflammatory pain in the rat

Plastic changes in the amygdala and limbic cortex networks have been widely shown in chronic pain. We have here investigated the role of group I metabotropic glutamate receptors (mGluRs) in the basolateral amygdala (BLA) pre-infra-limbic (PL-IL) divisions of the medial prefrontal cortex (mPFC) neuron connections after carrageenan-induced inflammatory pain in the rat. Intra-plantar injection of carrageenan decreased either spontaneous or mechanically/electrically evoked activity of PL cortex pyramidal neurons which responded with excitation in a way prevented by CPCOOEt, a selective mGluR1 antagonist, though not by MPEP, a selective mGluR5 antagonist. Accordingly, intra-BLA microinjection of DHPG, a group I mGluR agonist, caused PL cortex neuron activity depression, antagonized by CPCCOEt. CPCOOEt, but not MPEP, reduced also carrageenan-induced mechanical allodynia. The PL cortex cell deactivation in inflammatory pain condition was associated with increased GABA (conversely glutamate was decreased) in the PL/IL cortex. The local application of bicuculline, a GABAA receptor selective antagonist, reduced mechanical allodynia. An over-expression of mGluR1, but not mGluR5, have been observed in the PL-IL cortex after inflammatory pain suggesting an increased mGluR1-dependent cross-talk among BLA and IL-PL cortex neurons in inflammatory pain conditions. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. © 2012 Elsevier Ltd. All rights reserved

Investigations on the 4-Quinolone-3-carboxylic Acid Motif. 3. Synthesis, Structure-Affinity Relationships, and Pharmacological Characterization of 6-Substituted 4-Quinolone-3-carboxamides as Highly Selective Cannabinoid-2 Receptor Ligands

A set of quinolone-3-carboxamides 2 bearing diverse substituents at position 1, 3, and 6 of the bicyclic nucleus was prepared. Except for six compounds exhibiting Ki >100 nM, all the quinolone-3- carboxamides 2 proved to be high affinity CB2 ligands, with Ki values ranging from 73.2 to 0.7 nM and selectivity [SI=Ki(CB1)/Ki(CB2)] varying from >14285 to 1.9, with only 2ah exhibiting a reverse selectivity (SI<1). In the formalin test of peripheral acute and inflammatory pain in mice, 2ae showed analgesic activity that was antagonized by a selective CB2 antagonist. By contrast, 2e was inactive per se and antagonized the effect of a selective CB2 agonist. Finally, 2g and 2p exhibited CB2 inverse agonistlike behavior in this in vivo test. However, two different functional assays carried out in vitro on 2e and 2g indicated for both compounds an overall inverse agonist activity at CB2 receptors