The effects of pretreatment with pertussis toxin (PTX) on the sedative effect of morphine administered i.c.v. (200 nmol), and on the locomotor and behavioural activation precipitated by naloxone (15 mg/kg s.c.) following treatment with a single dose of morphine (i.c.v., 200 nmol), were investigated in guinea-pigs. Responses to i.c.v. administration of substance P (50 nmol), quinpirole (200 nmol), U50,488H (100 nmol) and carbachol (2 nmol) following PTX pretreatment were also investigated. Following PTX pretreatment, morphine induced mild agitation and the onset of sedation was delayed. Pretreatment with PTX also attenuated the locomotor and some components of behavioural activation induced by substance P, U50,488H, quinpirole and naloxone-precipitated morphine withdrawal, but failed to attenuate the effects induced by carbachol. These results suggest the involvement of PTX-sensitive G-protein-mediated mechanisms in the sedative effect of morphine in guinea-pigs and in the central stimulating actions of acute morphine withdrawal, U50,488H, substance P, and quinpirole.