Δ(9)-Tetrahydrocannbinol (
THC), the primary active constituent of Cannabis sativa, has long been known to reduce
opioid withdrawal symptoms. Although
THC produces most of its pharmacological actions through the activation of CB(1) and CB(2)
cannabinoid receptors, the role these receptors play in reducing the variety of
opioid withdrawal symptoms remains unknown. The endogenous
cannabinoids,
N-arachidonoylethanolamine (
anandamide; AEA) and
2-arachidonylglycerol (2-AG), activate both
cannabinoid receptors but are rapidly metabolized by
fatty acid amide hydrolase (FAAH) and
monoacylglycerol lipase (MAGL), respectively. The objective of this study was to test whether increasing AEA or 2-AG, via inhibition of their respective hydrolytic
enzymes, reduces
naloxone-precipitated
morphine withdrawal symptoms in in vivo and in vitro models of
opioid dependence.
Morphine-dependent mice challenged with
naloxone reliably displayed a profound withdrawal syndrome, consisting of jumping, paw
tremors,
diarrhea, and
weight loss.
THC and the MAGL inhibitor
4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)
piperidine-1-carboxylate (
JZL184) dose dependently reduced the intensity of most measures through the activation of CB(1) receptors.
JZL184 also attenuated spontaneous withdrawal signs in
morphine-dependent mice. The FAAH inhibitor N-(pyridin-3-yl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)benzyl)-piperdine-1-carboxamide (PF-3845) reduced the intensity of
naloxone-precipitated jumps and paw flutters through the activation of CB(1) receptors but did not ameliorate incidence of
diarrhea or
weight loss. In the final series of experiments, we investigated whether
JZL184 or
PF-3845 would attenuate
naloxone-precipitated contractions in
morphine-dependent ilea. Both
enzyme inhibitors attenuated the intensity of
naloxone-induced contractions, although this model does not account mechanistically for the autonomic withdrawal responses (i.e.,
diarrhea) observed in vivo. These results indicate that
endocannabinoid catabolic
enzymes are promising targets to treat
opioid dependence.