Chronic pain has become a severe global health issue. Pain associated with diabetic peripheral neuropathy (DPN), a common complication of diabetes, and is particularly treatment resistant. Classic therapeutic approaches demonstrate limited efficacy in cases of painful DPN (PDPN), associated side effects (e.g. tolerance, dependence) develop during chronic treatment make them less desirable for treating PDPN. Therefore, developing safe, efficacious and well-tolerated analgesics for PDPN is in critical need. Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels. Recently, potent and selective α9α10 nAChR antagonists, including neuropeptide α-conotoxins and small non-peptide molecules, have been investigated as safe and efficacious analgesics in multiple pain models, including neuropathic pain models. To expand the preclinical evaluation of these small molecules, in this dissertation, one lead α9α10 nAChR antagonist, ZZ204G was evaluated in normal and streptozotocin-induced diabetic rat pain models after acute and chronic treatment utilizing multiple nociception assays. Pharmacokinetic parameters were also determined after intravenous and intraperitoneal administration of ZZ204G to gain insights of its absorption, distribution, metabolism, and excretion in normal rats. Additional experiments using an opioid antagonist in combination with ZZ204G were conducted to provide more information on the possibility of opioid mechanisms of the antinociceptive action of ZZ204G. A computational model of the full α9α10 nAChR was established, and molecular interactions between the receptor and α9α10 nAChR antagonists were studied.
From these studies, we have identified ZZ204G as a potent and safe pain modulator in the treatment of acute and chronic pain conditions in normal and diabetic animals, with no development of tolerance or treatment-induced hyperalgesia. After i.p. administration, ZZ204G reached peak concentrations in plasma within 15 minutes, and most of the drug was eliminated in the urine. ZZ204G was not detected in the brain at 15 minutes post-i.p. administration. Opioid receptors are unlikely to be involved in the mechanism of action of α9α10 nAChR antagonists, since opioid antagonists do not alter the antinociceptive effects of ZZ204G. The computational docking studies have provided a full α9α10 nAChR model which can be used to design and screen novel drug-like α9α10 nAChR antagonists.
|Advisor:||Crooks, Peter A.|
|Commitee:||Breen, Philip J., Dobretsov, Maxim, Fifer, E. Kim, Thakkar, Shraddha|
|School:||University of Arkansas for Medical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 79/04(E), Dissertation Abstracts International|
|Keywords:||Antinociception, Diabetic neuropathy, Pain, Quaternary ammonium salts, α9α10 nicotinic acetylcholine receptors|
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