Browsing by Author "Papke, Roger L."
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Item The analgesic-like properties of the alpha7 nAChR silent agonist NS6740 is associated with non-conducting conformations of the receptor(Pergamon-Elsevier Science, 2015-04) Papke, Roger L.; Kulkarni, Abhijit R.; Gould, Timothy; Alsharari, Shakir D.; Thakur, Ganesh A.; Damaj, M.Imad; Bagdaş, Deniz; Uludağ Üniversitesi/Tıp Fakültesi/Deney Hayvanları Yetiştirme ve Araştırma Merkezi.; 15062425700The alpha 7 nicotinic acetylcholine receptor (nAChR) is a promising drug target for a number of neurological disorders including chronic pain and inflammatory diseases. Since alpha 7 can function as a ligand-gated ion channel, drug development initially focused on ligands that were selective activators of the alpha 7 ion channel. However, the best alpha 7 drugs for chronic pain and inflammation indications may not be ion channel activators but rather "silent agonists", which bind to the receptor but preferentially induce non-conducting states that modulate signal transduction in non-neuronal cells. One such compound is NS6740. We show that NS6740 selectively induces prolonged desensitization of alpha 7 nAChRs. There are two forms of alpha 7 desensitization that can be distinguished by their sensitivity to the positive allosteric modulators (PAMs). At high concentrations, NS6740 preferentially induces PAM-insensitive desensitization, which over the course of several minutes reverts to the sensitive form. NS6740 was tested in several pain models after in vivo administration in the mouse. Although it had no effects in acute thermal pain, NS6740 induced significant dose- and time-dependent antinociceptive activity in formalin- and acetic acid-induced nociceptive behaviors as well as in the chronic constrictive nerve injury (CCI) model for neuropathic pain. The antinociceptive activity of NS6740 in these models was alpha 7-dependent. In addition, NS6740 administration reversed pain-induced aversion, an important affective component of pain. The time and concentration dependence of the effects were consistent with NS6740 induction of PAM-insensitive non-conducting states, suggesting that signal transduction required for analgesia is accomplished by alpha 7 receptors in that conformation.Item New insights on neuronal nicotinic acetylcholine receptors as targets for pain and inflammation: A focus on α7 nAChRs(Bentham Science Publishers, 2017-08-16) Flood, Pamela; Papke, Roger L.; Damaj, M. Imad; Bağdaş, Deniz; Gürün, Mine Sibel; Uludağ Üniversitesi/Tıp Fakültesi/Deney Hayvanları Yetiştirme ve Araştırma Merkezi.; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji Anabilim Dalı.; AAG-8716-2019; EOB-5882-2022; 15062425700; 55664349700Background: Nicotine and nicotinic acetylcholine receptors (nAChRs) have been explored for the past three decades as targets for pain control. The aim of this review is to introduce readers particularly to alpha 7 nAChRs in a perspective of pain and its modulation. Methods: Developments for alpha 7 nAChR modulators and recent animal studies related to pain are reviewed. Results: Accumulating evidences suggest that selective ligands for alpha 7 nAChRs hold promise in the treatment of chronic pain conditions as they lack many of side effects associated with other nicotinic receptor types. Conclusion: This review provides the reader recent insights on alpha 7 nAChRs from structure and function to the latest findings on the pharmacology and therapeutic targeting of these receptors for the treatment of pain and inflammation.Item Persistent activation of α7 nicotinic ACh receptors associated with stable induction of different desensitized states(John Wiley and Sons Inc., 2018-06) Papke, Roger L.; Stokes, Clare; Damaj, M. Imad; Thakur, Ganesh A.; Manther, Khan; Treinin, Millet; Kulkarni, Abhijit R.; Horenstein, Nicole A.; Bağdaş, Deniz; Uludağ Üniversitesi/Tıp Fakültesi/Deney Hayvanları Yetiştirme ve Araştırma Merkezi.; EOB-5882-2022; 15062425700Background and Purpose: GAT107 ((3aR,4S,9bS)-4-(4-bromo-phenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta-[c]quinoline-8-sulfonamide) is a positive allosteric modulator (PAM) and agonist of α7 nicotinic acetylcholine receptors (nAChRs)that can cause a prolonged period of primed potentiation of acetylcholine responses after drug washout. NS6740 is a silent agonist of α7 nAChRs that has little or no efficacy for activating the ion channel but induces stable desensitization states, some of which can be converted into channel-active states by PAMs. Although GAT107 and NS6740 appear to stably induce different non-conducting states, both agents are effective treatment for inflammation and inflammatory pain models. We sought to better understand how both of these drugs that have opposite effects on channel activation could regulate signal transduction. Experimental Approach: Voltage-clamp experiments were conducted with α7 nAChRs expressed in Xenopus oocytes. Key Results: Long-lived sensitivity to a PAM or to an agonist was produced by NS6740 or GAT107 respectively. With sequential applications, these two drugs induced varying levels of persistent activation, which is a unique condition for a receptor that is known for rapid desensitization. The non-conducting states induced by NS6740 or GAT107 differ in their sensitivity to an α7 nAChR-selective antagonist and in how effectively they promote current. Conclusions & Implications: Our data suggest that the persistent currents represent a dynamic interconversion between different stable desensitized states and the PAM-inducible conducting states. However, the similarity of NS6740 and GAT107 effects on inflammation and pain suggests that the different stable non-conducting states have common activity on signal transduction.Item The α7 nicotinic receptor dual allosteric agonist and positive allosteric modulator GAT107 reverses nociception in mouse models of inflammatory and neuropathic pain(Wiley, 2016-05-17) Wilkerson, Jenny L.; Kulkarni, Abhijit; Toma, Wisam; AlSharari, Shakir; Lichtman, Aron H.; Papke, Roger L.; Thakur, Ganesh A.; Damaj, M. Imad; Bağdaş, Deniz; Gül, Zülfiye; Uludağ Üniversitesi/Tıp Fakültesi/Deney Hayvanları Yetiştirme ve Araştırma Merkezi.; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji Anabilim Dalı.; 0000-0002-8872-0074; AAF-9939-2020; 15062425700; 56086542900Background and PurposeOrthosteric agonists and positive allosteric modulators (PAMs) of the 7 nicotinic ACh receptor (nAChR) represent novel therapeutic approaches for pain modulation. Moreover, compounds with dual function as allosteric agonists and PAMs, known as ago-PAMs, add further regulation of receptor function. Experimental ApproachInitial studies examined the 7 ago-PAM, GAT107, in the formalin, complete Freund's adjuvant (CFA), LPS inflammatory pain models, the chronic constriction injury neuropathic pain model and the tail flick and hot plate acute thermal nociceptive assays. Additional studies examined the locus of action of GAT107 and immunohistochemical markers in the dorsal horn of the spinal cord in the CFA model. Key ResultsComplementary pharmacological and genetic approaches confirmed that the dose-dependent antinociceptive effects of GAT107 were mediated through 7 nAChR. However, GAT107 was inactive in the tail flick and hot plate assays. In addition, GAT107 blocked conditioned place aversion elicited by acetic acid injection. Furthermore, intrathecal, but not intraplantar, injections of GAT107 reversed nociception in the CFA model, suggesting a spinal component of action. Immunohistochemical evaluation revealed an increase in the expression of astrocyte-specific glial fibrillary acidic protein and phosphorylated p38MAPK within the spinal cords of mice treated with CFA, which was attenuated by intrathecal GAT107 treatment. Importantly, GAT107 did not elicit motor impairment and continued to produce antinociceptive effects after subchronic administration in both phases of the formalin test. Conclusions and ImplicationsCollectively, these results provide the first proof of principle that 7 ago-PAMs represent an effective pharmacological strategy for treating inflammatory and neuropathic pain.