The periaqueductal grey (PAG) has been shown to be a major source of descending inhibition of dorsal horn cells (Textbook of Pain (1999) 309). However, few studies have demonstrated alterations in behavioural responses to noxious stimulation following inactivation of this nucleus. Many behavioural studies have looked for effects on nociceptive withdrawal thresholds in acute nociceptive tests. These tests would not reveal the presence of inhibition which is activated in response to noxious input. We have therefore investigated this possibility by studying behavioural responses to subcutaneous formalin injection in control animals, and in animals following partial sciatic nerve ligation (an animal model of neuropathic pain (Pain 43(2) (1990) 205). In control animals, microinjection of gamma-aminobutyric acid (GABA) to PAG did not significantly alter behavioural responses to formalin, while microinjection of D,L-homocysteic acid (DLH) reduced these responses. Responses to contralaterally applied formalin were significantly reduced in animals with partial sciatic ligation. Microinjection of GABA to PAG significantly increased these behavioural responses to formalin. We conclude that a component of PAG mediated inhibition of nociception is inactive under normal conditions. This inhibition may be activated by persistent nociceptive input, and possibly reflects long term changes in nociceptive circuitry which occur in neuropathic pain states.