We used the tail-flick response of rats to study the role of opioid receptors in illness-induced hyperalgesia. An intraperitoneal injection of lithium chloride (LiCl) produced hyperalgesia that was blocked in a dose-dependent manner by subcutaneous injection of the opioid antagonist naloxone. Neither hyperalgesia nor its blockade by naloxone were due to variations in tail-skin temperature induced by LiCl. Hyperalgesia was also blocked when opioid receptor antagonism was restricted to (a) the periphery, by intraperitoneal administration of the quaternary opioid receptor antagonist naloxone methiodide; (b) the brain, by intracerebroventricular microinjection of naloxone; or (c) the spinal cord, by intrathecal microinjection of naloxone. These results document a pain facilitatory role of opioid receptors in both the peripheral and central nervous systems and are discussed with reference to their analgesic and motivational functions.