Progressive enhancement of delayed hyperalgesia induced by repeated heroinadministration: A sensitization process

It is difficult to conceive that tolerance and sensitization processes, two apparently opposite phenomena, can concomitantly modify one given biologic al process, i.e., the processing of pain. We have shown recently that opiat es produce not only analgesia but also long-lasting hyperalgesia in rats. T his suggests that tolerance to the analgesic effect of an opiate, especiall y heroin, could be in part the result of an actual sensitization of pronoci ceptive systems. Here, we show that both magnitude and duration of heroin-i nduced delayed hyperalgesia increase with intermittent heroin administratio ns, leading to an apparent decrease in the analgesic effectiveness of a giv en heroin dose. Our observation that a small dose of heroin which is ineffe ctive for triggering a delayed hyperalgesia in non-heroin-treated rats indu ced an enhancement in pain sensitivity for several days after a series of h eroin administrations is in agreement with the sensitization hypothesis. Th e effectiveness of the opioid receptor antagonist naloxone to precipitate h yperalgesia in rats that had recovered their pre-drug nociceptive value aft er single or repeated heroin administrations indicates that heroin-deprived rats were in a new biological state associated with a high level balance b etween opioid-dependent analgesic systems and pronociceptive systems. Becau se the NMDA receptor antagonist dizocilpine maleate (MK-801) prevented both heroin-induced long-lasting enhancement in pain sensitivity and naloxone-p recipitated hyperalgesia, these findings further suggest that tolerance, se nsitization, and one withdrawal symptom, hyperalgesia, are issued from a ne uroadaptive process in which NMDA systems play a critical role.