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. 2018 Jun;159(6):1155-1165.
doi: 10.1097/j.pain.0000000000001199.

Evaluation of Different Drug Classes on Transient Sciatic Nerve Injury-Depressed Marble Burying in Mice

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Free PMC article

Evaluation of Different Drug Classes on Transient Sciatic Nerve Injury-Depressed Marble Burying in Mice

Jenny L Wilkerson et al. Pain. .
Free PMC article

Abstract

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.

Figures

Figure 1
Figure 1
Mice subjected to CCI surgery bury fewer marbles and spend less time digging than sham mice. A) On post-surgical days 3 and 6, mice in the CCI condition bury fewer marbles than mice in sham surgery group, but marble burying is normalized by day 10. B) CCI surgery leads to reductions in time spent digging on post-surgical days 3 and 6, and digging behavior is again normalized by day 10. C) The time spent digging and number of marbles buried from panels A and B were highly correlated (r = 0.84). *** P < 0.0001, ** P < 0.005, * P < 0.05 vs. sham. Data reflect mean ± SEM, n=8 mice per group.
Figure 2
Figure 2
Standard analgesics reverse pain-depressed marble burying and pain-stimulated allodynia and thermal hyperalgesia. Morphine, valdecoxib and gabapentin dose-dependently reverse CCI-induced A) decreases in marble burying, B) thermal hyperalgesia, C) allodynia. Filled symbols denote significance from CCI controls, (P < 0.05). D) Morphine (10 mg/kg) does not affect marble burying behavior in vehicle treated mice and does not alter U69593 (0.1 mg/kg)-induced decreases in marble burying. ** P < 0.001, vs. vehicle – vehicle. Data reflect mean ± SEM, n = 6–18 mice/group.
Figure 3
Figure 3
Diazepam and U69593 decrease marble burying behavior but show differential effects in pain-stimulated behavioral assays. A) Neither diazepam nor U69593 reverse decreases in marble burying, but further decreased marble burying at the highest doses tested. B) U69593, but not diazepam reversed thermal hyperalgesia C) and allodynia. Filled symbols denote significance from CCI controls, (P < 0.05). Data reflect mean ± SEM, n = 6–8 mice/group.
Figure 4
Figure 4
Drugs targeting different components of the endogenous cannabinoid system differentially reverse CCI-induced nociceptive behavior. The mixed CB1/CB2 receptor agonist CP55,940, the selective CB2 receptor agonist LEI101, and the MAGL inhibitor MJN110 dose-dependently reverse CCI-induced decreases in A) marble burying, B) thermal hyperalgesia, and C) mechanical allodynia. The FAAH inhibitor PF3845 does not reverse CCI-induced depression of A) marble burying but reverses CCI-induced B) thermal hyperalgesia and C) mechanical allodynia. Filled symbols denote significance from CCI controls, (P < 0.05). Data reflect mean ± SEM, n = 6 mice/group.

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