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Evaluation of different drug classes on transient sciatic nerve injury–depressed marble burying in mice

Wilkerson, Jenny, L.a,*; Curry, Zachary, A.a; Kinlow, Pamela, D.a; Mason, Brittany, L.a; Hsu, Ku-Lungb; van der Stelt, Marioc; Cravatt, Benjamin, F.d; Lichtman, Aron, H.a

doi: 10.1097/j.pain.0000000000001199
Research Paper

A great need exists for the identification of new effective analgesics to treat sustained pain. However, most preclinical nociceptive assays measure behavioral responses evoked by noxious stimuli (ie, pain-stimulated behavior), which presents a challenge to distinguish between motor impairing and antinociceptive effects of drugs. Here, we demonstrate that chronic constriction injury (CCI) of the sciatic nerve elicits common pain-stimulated responses (ie, mechanical allodynia and thermal hyperalgesia) as well as reduces marble burying/digging behaviors that occur during the early stages of the neuropathy and resolve within 1 week. Although drugs representing distinct classes of analgesics (ie, morphine, valdecoxib, and gabapentin) reversed both CCI-induced and CCI-depressed nociceptive measures, diazepam lacked antinociceptive effects in all assays and the kappa-opioid receptor agonist U69593 reversed pain-stimulated, but not pain-depressed behaviors. In addition, we tested drugs targeting distinct components of the endocannabinoid system, including agonists at cannabinoid receptors type 1 (CB1) and type 2 (CB2), as well as inhibitors of the endocannabinoid-regulating enzymes fatty acid amide hydrolase and monoacylglycerol lipase. Each of these drugs reversed all CCI-induced nociceptive measures, with the exception of the fatty acid amide hydrolase inhibitor that reversed pain-stimulated behaviors, only. These findings support the use of the mouse marble-burying assay as a model of pain-depressed behavior within the first week of sciatic nerve injury to examine candidate analgesics. These data also support existing preclinical research that cannabinoid receptor agonists and inhibitors of endocannabinoid-regulating enzymes merit consideration for the treatment of pain.

Chronic constriction injury and spared nerve injury surgery transiently decrease marble burying behavior and time spent digging. Antinociceptive drugs reverse chronic constriction injury–induced depression of marble burying, thermal hyperalgesia, and mechanical allodynia.

aDepartment of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA

bDepartment of Chemistry, University of Virginia, Charlottesville, VA, USA

cDepartment of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands

dDepartment of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA

Corresponding author. Address: Department of Pharmacology and Toxicology, Virginia Commonwealth University, P.O. Box 980613, Richmond, VA 23298-0613, USA. Tel.: +1(352) 294-8908; fax: +1(804) 827-0377. E-mail address: jenny.wilkerson@cop.ufl.edu (J.L. Wilkerson).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

Received December 17, 2017

Received in revised form February 21, 2018

Accepted February 28, 2018

© 2018 International Association for the Study of Pain
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