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

Kieran Rea, Gemma K. Ford, Weredeselam M. Olango, Brendan Harhen, Michelle Roche, David P. Finn

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.