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An endocannabinoid mechanism for stress-induced analgesia


Acute stress suppresses pain by activating brain pathways that engage opioid or non-opioid mechanisms. Here we show that an opioid-independent form of this phenomenon, termed stress-induced analgesia1, is mediated by the release of endogenous marijuana-like (cannabinoid) compounds in the brain. Blockade of cannabinoid CB1 receptors in the periaqueductal grey matter of the midbrain prevents non-opioid stress-induced analgesia. In this region, stress elicits the rapid formation of two endogenous cannabinoids, the lipids 2-arachidonoylglycerol2 (2-AG) and anandamide3. A newly developed inhibitor of the 2-AG-deactivating enzyme, monoacylglycerol lipase4,5, selectively increases 2-AG concentrations and, when injected into the periaqueductal grey matter, enhances stress-induced analgesia in a CB1-dependent manner. Inhibitors of the anandamide-deactivating enzyme fatty-acid amide hydrolase6, which selectively elevate anandamide concentrations, exert similar effects. Our results indicate that the coordinated release of 2-AG and anandamide in the periaqueductal grey matter might mediate opioid-independent stress-induced analgesia. These studies also identify monoacylglycerol lipase as a previously unrecognized therapeutic target.

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Figure 1: CB 1 receptors mediate non-opioid stress-induced analgesia.
Figure 2: Stress stimulates the formation of 2-AG and anandamide in dorsal midbrain.
Figure 3: URB602 is a selective MGL inhibitor.
Figure 4: The MGL inhibitor URB602 enhances non-opioid stress-induced analgesia.
Figure 5: Inhibitors of anandamide hydrolysis (URB597) and transport (VDM11) enhance non-opioid stress-induced analgesia.


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The assistance of the Centro di Calcolo at the University of Parma is gratefully acknowledged. This research was supported by grants from the National Institute on Drug Abuse (A.G.H., D.P.) and from the MIUR and the Universities of Parma and Urbino ‘Carlo Bo’.

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Correspondence to Andrea G. Hohmann or Daniele Piomelli.

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A patent has been filed on their behalf by the University of California at Irvine.

Supplementary information

Supplementary Figure S1

Systemic administration of the CB1 antagonist AM251 suppresses non-opioid stress-induced antinociception. (PDF 9 kb)

Supplementary Figure S2

Rimonabant does not alter tail-flick latencies in the absence of the stressor. (PDF 8 kb)

Supplementary Figure S3

Non-opioid stress-induced antinociception is unaffected by morphine tolerance. (PDF 7 kb)

Supplementary Figure S4

Rimonabant does not alter stress-induced antinociception following microinjection in the lateral/ventrolateral PAG. (PDF 29 kb)

Supplementary Figure S5

Administration of rimonabant into the lateral ventricle does not affect opioid-independent stress-induced antinociception. (PDF 10 kb)

Supplementary Figure S6

Representative LC/MS tracings for selected ions characteristic of endogenous 2-AG, synthetic [2H8]-2-AG standard, endogenous anandamide and synthetic [2H4]-2-anandamide standard. (PDF 33 kb)

Supplementary Figure S7

Coronal reconstructions of injection sites following microinjection of URB602 in the (a) dorsolateral or (b,c) lateral/ventrolateral PAG. (PDF 80 kb)

Supplementary Figure S8

Coronal reconstructions of injection sites following microinjection of URB597 in the dorsolateral PAG. (PDF 41 kb)

Supplementary Figure S9

Inhibition of MGL enhances nonopioid stress-induced analgesia. (PDF 54 kb)

Supplementary Figure S1 Legend (DOC 22 kb)

Supplementary Figure S2 Legend (DOC 21 kb)

Supplementary Figure S3 Legend (DOC 22 kb)

Supplementary Figure S4 Legend (DOC 22 kb)

Supplementary Figure S5 Legend (DOC 21 kb)

Supplementary Figure S6 Legend (DOC 24 kb)

Supplementary Figure S7 Legend (DOC 22 kb)

Supplementary Figure S8 Legend (DOC 21 kb)

Supplementary Figure S9 Legend (DOC 25 kb)

Supplementary Methods (DOC 31 kb)

Supplementary Table (DOC 32 kb)

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Hohmann, A., Suplita, R., Bolton, N. et al. An endocannabinoid mechanism for stress-induced analgesia. Nature 435, 1108–1112 (2005).

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