Evidence for differential modulation of conditioned aversion and fear-conditioned analgesia by CB₁ receptors

Fear-conditioned analgesia is an important survival response mediated by substrates controlling nociception and aversion. Cannabinoid₁ (CB₁) receptors play an important role in nociception and aversion. However, their role in fear-conditioned analgesia has not been investigated. This study investigated the effects of systemic administration of the CB ₁ receptor antagonist, SR141716A (1 mg/kg, ip), on fear-conditioned analgesia and conditioned aversion in rats. Twenty-four hours after receiving footshock, rats exhibited reduced formalin-evoked nociceptive behaviour, increased freezing and increased defecation when tested in the footshock apparatus, compared with non-footshocked formalin-injected rats. SR141716A attenuated fear-conditioned analgesia, freezing and defecation. Importantly, SR141716A had no effect on formalin-evoked nociceptive behaviour over an equivalent time period in rats not receiving footshock. SR141716A had no effect on contextually induced freezing during the first half of the test trial in rats receiving intra-plantar injection of saline. Administration of SR1417176A did, however, attenuate short-term extinction of contextually induced freezing and ultrasound emission in rats receiving intra-plantar saline, compared with vehicle-treated saline controls. These data suggest an important role for the CB₁ receptor in mediating fear-conditioned analgesia and provide evidence for differential modulation of conditioned aversive behaviour by CB₁ receptors during tonic, persistent pain.