Opiate tolerance to daily heroin administration : An apparent phenomenon associated with enhanced pain sensitivity

Abstract From a classical viewpoint, tolerance to analgesic effects of opiates refers to the decreased effectiveness of a given opiate following its repeated use. [11] Despite much research, it has not been conclusively demonstrated in vivo that functional changes observed at the opioid receptor level in the responsiveness to opiates account for development of tolerance. 2 , 9 , 10 , 36 An alternative hypothesis is that opioid receptors remain operative following repeated opiate administration but that opioid receptor activation rapidly induces a prolonged increase in pain sensitivity which opposes the predominant opiate analgesic effect following repeated opiate administration. We recently showed that a single heroin administration induces an enhanced pain sensitivity for several days, [27] a phenomenon which is prevented by the non-competitive N -methyl- d -aspartate receptor antagonist MK-801. Herein we report that repeated once-daily heroin injections induced a gradual lowering of the nociceptive threshold which progressively masked a sustained heroin analgesic functional effect. MK-801 prevented such opiate-induced allodynia and thereby prevented development of an apparent decrease in the effectiveness of heroin. These results indicate that intermittent heroin administration induced a persistent increase in the basal pain sensitivity which, if not taken into account gives the impression of less analgesia, i.e. apparent tolerance.