title: Analgesic properties of a peripherally acting and GalR2 receptor-preferring galanin analog in inflammatory, neuropathic, and acute pain models.
abstract: There are ongoing efforts to develop pain therapeutics with novel mechanisms of action that avoid common side effects associated with other analgesics. The anticonvulsant neuropeptide galanin is a potent regulator of neuronal excitability and has a well established role in pain modulation, making it a potential target for novel therapies. Our previous efforts focused on improving blood-brain-barrier penetration and enhancing the metabolic stability of galanin analogs to protect against seizures. More recently, we designed peripherally acting galanin analogs that reduce pain-related behaviors by acting in the periphery and exhibit preferential binding toward galanin receptor (GalR)2 over GalR1. In this study, we report preclinical studies of a monodisperse oligoethylene glycol-containing galanin analog, NAX 409-9 (previously reported as GalR2-dPEG24), in rodent analgesic and safety models. Results obtained with NAX 409-9 in these tests were compared with the representative analgesics gabapentin, ibuprofen, acetylsalicylic acid, acetaminophen, and morphine. In mice that received intraplantar carrageenan, NAX 409-9 increased paw withdrawal latency with an ED50 of 6.6 mg/kg i.p. NAX 409-9 also increased the paw withdrawal threshold to mechanical stimulation following partial sciatic nerve ligation in rats (2 mg/kg). Conversely, NAX 409-9 had no effect in the tail flick or hot plate assays (up to 24 mg/kg). Importantly, NAX 409-9 did not negatively affect gastrointestinal motility (4-20 mg/kg), respiratory rate (40-80 mg/kg), or bleed time (20 mg/kg). These studies illustrate that this nonbrain-penetrating galanin analog reduces pain behaviors in several models and does not produce some of the dose-limiting toxicities associated with other analgesics.
authors.affiliation: Neuroadjuvants, Inc., Salt Lake City, Utah (C.S.M., B.D.K., D.R.M.); and Departments of Pharmacology and Toxicology (B.D.K., M.D.S., H.S.W.) and Medicinal Chemistry (L.Z., G.B.), College of Pharmacy, University of Utah, Salt Lake City, Utah.
authors.forename: Cameron S
authors.initials: CS
authors.lastname: Metcalf
authors.affiliation: Neuroadjuvants, Inc., Salt Lake City, Utah (C.S.M., B.D.K., D.R.M.); and Departments of Pharmacology and Toxicology (B.D.K., M.D.S., H.S.W.) and Medicinal Chemistry (L.Z., G.B.), College of Pharmacy, University of Utah, Salt Lake City, Utah.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Klein
authors.affiliation: Neuroadjuvants, Inc., Salt Lake City, Utah (C.S.M., B.D.K., D.R.M.); and Departments of Pharmacology and Toxicology (B.D.K., M.D.S., H.S.W.) and Medicinal Chemistry (L.Z., G.B.), College of Pharmacy, University of Utah, Salt Lake City, Utah.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: McDougle
authors.affiliation: Neuroadjuvants, Inc., Salt Lake City, Utah (C.S.M., B.D.K., D.R.M.); and Departments of Pharmacology and Toxicology (B.D.K., M.D.S., H.S.W.) and Medicinal Chemistry (L.Z., G.B.), College of Pharmacy, University of Utah, Salt Lake City, Utah.
authors.forename: Liuyin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Neuroadjuvants, Inc., Salt Lake City, Utah (C.S.M., B.D.K., D.R.M.); and Departments of Pharmacology and Toxicology (B.D.K., M.D.S., H.S.W.) and Medicinal Chemistry (L.Z., G.B.), College of Pharmacy, University of Utah, Salt Lake City, Utah.
authors.forename: Misty D
authors.initials: MD
authors.lastname: Smith
authors.affiliation: Neuroadjuvants, Inc., Salt Lake City, Utah (C.S.M., B.D.K., D.R.M.); and Departments of Pharmacology and Toxicology (B.D.K., M.D.S., H.S.W.) and Medicinal Chemistry (L.Z., G.B.), College of Pharmacy, University of Utah, Salt Lake City, Utah.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Bulaj
authors.affiliation: Neuroadjuvants, Inc., Salt Lake City, Utah (C.S.M., B.D.K., D.R.M.); and Departments of Pharmacology and Toxicology (B.D.K., M.D.S., H.S.W.) and Medicinal Chemistry (L.Z., G.B.), College of Pharmacy, University of Utah, Salt Lake City, Utah steve.white@hsc.utah.edu.
authors.forename: H Steve
authors.initials: HS
authors.lastname: White
mesh_terms: D059787:Acute Pain / Q000188:drug therapy* / Q000378:metabolism; D000595:Amino Acid Sequence; D000700:Analgesics / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001760:Bleeding Time; D002351:Carrageenan / Q000009:adverse effects; D004195:Disease Models, Animal; D019004:Galanin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D017933:Peripheral Nervous System / Q000187:drug effects*; D051381:Rats; D044092:Receptor, Galanin, Type 2 / Q000378:metabolism*
chemical_list: D000700:Analgesics; D044092:Receptor, Galanin, Type 2; D019004:Galanin; D002351:Carrageenan