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

Wilkerson, J.L.; Curry, Z.A.; Kinlow, P.D.; Mason, B.L.; Hsu, K.L.; Stelt, M. van der; Cravatt, B.F.; Lichtman, A.H.

doi:doi:10.1097/j.pain.0000000000001199

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 (i.e., pain-stimulated behavior), which presents a challenge to distinguish between motor impairing and antinociceptive effects of drugs. Here, we demonstrate that chronic constriction injury of the sciatic nerve (CCI) elicits common pain-stimulated responses (i.e., 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 one week. Whereas drugs representing distinct classes of analgesics (i.e., 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...Show moreA 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 (i.e., pain-stimulated behavior), which presents a challenge to distinguish between motor impairing and antinociceptive effects of drugs. Here, we demonstrate that chronic constriction injury of the sciatic nerve (CCI) elicits common pain-stimulated responses (i.e., 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 one week. Whereas drugs representing distinct classes of analgesics (i.e., 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 (FAAH), monoacylglycerol lipase (MAGL). Each of these drugs reversed all CCI-induced nociceptive measures, with the exception of the FAAH 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.Show less

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