The monoacylglycerol lipase inhibitor KML29 with gabapentin synergistically produces analgesia in mice.

ABSTRACT:

Background and purpose

Gabapentin is commonly prescribed for nerve pain but may also cause dizziness, sedation and gait disturbances. Similarly, inhibition of the endogenous cannabinoid enzyme monoacylglycerol lipase (MAGL) has antinociceptive and anti-inflammatory properties but also induces sedation in mice at high doses. To limit these side effects, the present study investigated the analgesic effects of coadministering a MAGL inhibitor with gabapentin.

Experimental approach

Mice subjected to the chronic constriction injury model of neuropathic pain were administered the MAGL inhibitor KML29 (1-40 mg·kg^-1 , i.p.), gabapentin (1-50 mg·kg^-1 , i.p.) or both compounds. Mice were tested for mechanical and cold allodynia. The function and expression of cannabinoid CB₁ receptors in whole brain homogenates and lipid profile of spinal cords were assessed after repeated drug administration.

Key results

The combination of low-dose KML29:gabapentin additively attenuated mechanical allodynia and synergistically reduced cold allodynia. The CB₁ antagonist, rimonabant, partially reversed the anti-allodynic effects of KML29:gabapentin in mechanical allodynia but not cold allodynia. The anti-allodynic effects of KML29:gabapentin did not undergo tolerance in mechanical allodynia after repeated administration but produced mild tolerance in cold allodynia. High dose KML29 alone reduced CB₁ receptor expression and function, but KML29:gabapentin reduced the density of CB₁ receptors but did not alter their function. KML29:gabapentin influenced additional signalling pathways (including fatty acids) other than the pathways activated by a higher dose of either drug alone.

Conclusion and implications

These data support the strategy of combining MAGL inhibition with a commonly prescribed analgesic as a therapeutic approach for attenuating neuropathic pain.

SUBMITTER: Crowe MS 

PROVIDER: S-EPMC5715597 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature