Background and PurposeThe emotional processing and coordination of top-down responses to noxious and conditioned aversive stimuli involves the medial prefrontal cortex (mPFC). Evidence suggests that subregions of the mPFC [infralimbic (IfL), prelimbic (PrL) and anterior cingulate (ACC) cortices] differentially alter the expression of contextually induced fear and nociceptive behaviour. We investigated the role of the endocannabinoid system in the IfL, PrL and ACC in formalin-evoked nociceptive behaviour, fear-conditioned analgesia (FCA) and conditioned fear in the presence of nociceptive tone.Experimental ApproachFCA was modelled in male Lister-hooded rats by assessing formalin-evoked nociceptive behaviour in an arena previously paired with footshock. The effects of intra-mPFC administration of AM251 [cannabinoid type 1 (CB1) receptor antagonist/inverse agonist], URB597 [fatty acid amide hydrolase (FAAH) inhibitor] or URB597+AM251 on FCA and freezing behaviour were assessed.Key ResultsAM251 attenuated FCA when injected into the IfL or PrL and reduced contextually induced freezing behaviour when injected intra-IfL but not intra-PrL or intra-ACC. Intra-ACC administration of AM251 alone or in combination with URB597 had no effect on FCA or freezing. URB597 attenuated FCA and freezing behaviour when injected intra-IfL, prolonged the expression of FCA when injected intra-PrL and had no effect on these behaviours when injected intra-ACC.Conclusions and ImplicationsThese results suggest important and differing roles for FAAH substrates or CB1 receptors in the PrL, IfL and ACC in the expression of FCA and conditioned fear in the presence of nociceptive tone.