The prefrontal cortical endocannabinoid system modulates fear-pain interactions in a subregion-specific manner

The 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.

FCA 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.

AM251 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.

These 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.

This article is part of a themed section on 8^th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc.