Kieran Rea, Gemma K. Ford, Weredeselam M. Olango, Brendan Harhen, Michelle Roche and David P. Finn
Schematic depicting the role of the vHip in both contextual fear conditioning and pain processing and the putative neural circuitry and mechanisms mediating the effects of intra-vHip 2-AG injection observed in the present study. The vHip shares connectivity with the lateral amygdala (LA), basolateral amygdala (BLA) and central nucleus of the amygdala (CeA), as well as cortical regions, from which neurons project to the periaqueductal gray (PAG) to regulate the behavioural expression of pain and fear. The re-exposure of an animal to an environment where it has previously been exposed to footshock recruits neurons in the vHip, amygdala and cortical regions to engage neurons in the PAG, resulting in the expression of conditioned fear. Upon activation of peripheral nociceptors by a noxious stimulus, nociceptive information is relayed through the dorsal horn of the spinal cord, and reaches higher centres in the brain. The ventrolateral aspect of the periaqueductal gray (vlPAG) is critically involved in the expression of contextual fear and formalin-evoked nociception. AEA (anandamide) and 2-AG (2-arachidonoyl glycerol) levels were significantly decreased in left vlPAG of fear-conditioned, formalin-treated rats i.e. the vlPAG side contralateral to the hindpaw into which formalin was injected. The suppression of conditioned freezing as a consequence of CB1 receptor activation in the vHip by 2-AG was not apparent in formalin-treated rats. These differential effects of intra-vHip 2-AG on conditioned fear responding in the absence versus presence of formalin-evoked nociceptive tone do not appear to be due to formalin-evoked alterations in levels of endocannabinoids locally in the vHip but may be related to the formalin-evoked reduction in endocannabinoid levels observed in the contralateral vlPAG. CB1R: cannabinoid receptor type 1, AEA: anandamide, 2-AG: 2-arachidonoyl glycerol, vHip: ventral hippocampus, CeA: central nucleus of the amygdala, LA: lateral amygdala, BLA: basolateral amygdala, vlPAG: ventrolateral periaqueductal gray, RVM: rostral ventromedial medulla, FC: fear-conditioned, Form: formalin.