Lever pressing of monkeys was maintained under a titration schedule in which responses decreased shock intensity which otherwise was increased at a fixed rate. The opioid morphine, the antihypertensive clonidine and the cannabinoid l-nantradol each resulted in a dose-related increase in shock intensity, although l-nantradol and clonidine were 10 to 30 times more potent than morphine. Morphine and l-nantradol resulted in markedly higher shock intensities only at doses that severely disrupted responding, whereas clonidine resulted in higher shock intensities over a broader dose range without disrupting responding. Marked tolerance developed for the shock-increasing effects of morphine (3.0 mg/kg) and l-nantradol (0.3 mg/kg) within 10 to 15 sessions, but only partial tolerance developed for shock-increasing effects of clonidine (0.3 mg/kg) after up to 35 sessions. The shock-increasing effects of chronically administered clonidine were antagonized by the alpha-2 adrenoceptor antagonist yohimbine but not by the alpha-1 adrenoceptor antagonist prazosin. When effects of acute injections were redetermined after 1 month without drug, the effects of clonidine, but not morphine or l-nantradol, were the same as before chronically administered drug. The influence of behavioral processes on the long-lasting effects of drugs seemed greater for morphine and l-nantradol than for clonidine.