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.
Footnotes
- Received August 7, 2014.
- Accepted October 24, 2014.
This work was supported in part by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant R21-NS059669 to G.B. and H.S.W.].
G.B. and H.S.W. are scientific cofounders of Neuroadjuvants, Inc.
Some of the data presented in this work has been previously presented as follows: Metcalf CS, Klein BD, McDougle DR, Bulaj G, and White HS (2012) Antinociceptive effects of novel GalR2-specific analogs. Experimental Biology 2012; 2012 Apr 21–25; San Diego, CA. American Society for Pharmacology and Experimental Therapeutics; and Metcalf CS, Klein BD, McDougle DR, Zhang L, Smith MD, Bulaj G, and White HS (2013) Development of peripherally-acting, GalR2-preferring galanin analogs for the treatment of pain. Galanin SFN Pre-Meeting 2013; 2013 Nov 8–9; San Diego, CA.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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