The endocannabinoid system controls fear and pain differently depending on which part of the prefrontal cortex is involved

The CB1 receptor antagonist AM251 attenuated fear-conditioned analgesia (FCA) when injected into the infralimbic or prelimbic cortex, but reduced freezing only in the infralimbic region. The FAAH inhibitor URB597 attenuated FCA and freezing in the infralimbic cortex but prolonged FCA in the prelimbic cortex. Neither drug had effects in the anterior cingulate cortex.

Male rats received intra-prefrontal cortex microinjections of AM251 (CB1 antagonist), URB597 (FAAH inhibitor), or combination, then underwent formalin-evoked pain testing in a fear-conditioned arena previously paired with footshock.

The endocannabinoid system is a drug target for both pain and anxiety. This study reveals that its role varies dramatically even within adjacent brain subregions, which has implications for precision medicine approaches.

Cannabis affects pain and fear/anxiety, but not always in the same direction for everyone. This study shows part of the reason: even within the prefrontal cortex, the endocannabinoid system plays different and sometimes opposing roles depending on the exact location.

Rat study using microinjections that do not replicate systemic cannabis use. Only male rats were tested. The pharmacological tools used (AM251, URB597) affect endocannabinoids broadly, not just anandamide.