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The analgesic potential of cannabinoids may be hampered by their ability to produce aversive emotion when administered systemically. We investigated the hypothesis that the midbrain periaqueductal grey (PAG) is a common substrate mediating the anti-nociceptive and potential aversive effects of cannabinoids. The rat formalin test was used to model nociceptive behaviour. Intra-PAG microinjection of the excitatory amino acid d,l-homocysteic acid (DLH) was used to induce an aversive, panic-like reaction characteristic of the defensive “fight or flight” response. Administration of the cannabinoid receptor agonist HU210 (5 μg/rat) into the dorsal PAG significantly reduced the second phase of formalin-evoked nociceptive behaviour, an effect which was blocked by co-administration of the CB₁ receptor antagonist SR141716A (50 μg/rat). This anti-nociceptive effect was accompanied by an HU210-induced attenuation …