Microinjection of 2‐arachidonoyl glycerol into the rat ventral hippocampus differentially modulates contextually induced fear, depending on a persistent pain state

The endogenous cannabinoid (endocannabinoid) system plays a key role in the modulation of aversive and nociceptive behaviour. The components of the endocannabinoid system are expressed throughout the hippocampus, a brain region implicated in both conditioned fear and pain. In light of evidence that pain can impact on the expression of fear‐related behaviour, and vice versa, we hypothesised that exogenous administration of the endocannabinoid 2‐arachidonoyl glycerol (2‐AG) into the ventral hippocampus (vHip) would differentially regulate fear responding in the absence vs. the presence of formalin‐evoked nociceptive tone. Fear‐conditioned rats showed significantly increased freezing and a reduction in formalin‐evoked nociceptive behaviour upon re‐exposure to a context previously paired with footshock. Bilateral microinjection of 2‐AG into the vHip significantly reduced contextually induced freezing in non‐formalin‐treated rats, and reduced formalin‐evoked nociceptive behaviour in non‐fear‐conditioned rats. In contrast, 2‐AG microinjection had no effect on fear responding in formalin‐treated rats, and no effect on nociceptive behaviour in fear‐conditioned rats. The inhibitory effect of 2‐AG on fear‐related behaviour, but not pain‐related behaviour, was blocked by co‐administration of the cannabinoid receptor 1 (CB1) antagonist/inverse agonist rimonabant. Tissue levels of the endocannabinoids N‐arachidonoylethanolamide (anandamide, AEA) and 2‐AG were similar in the vHip of fear‐conditioned rats receiving formalin injection and the vHip of fear‐conditioned rats receiving saline injection. However, the levels of AEA and 2‐AG were significantly lower in the contralateral ventrolateral periaqueductal grey of formalin‐treated fear‐conditioned rats than in that of their saline‐treated counterparts. These data suggest that 2‐AG–CB1 receptor signalling in the vHip has an anti‐aversive effect, and that this effect is abolished in the presence of a persistent pain state.

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