title: Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration: a sensitization process.
abstract: It is difficult to conceive that tolerance and sensitization processes, two apparently opposite phenomena, can concomitantly modify one given biological process, i.e., the processing of pain. We have shown recently that opiates produce not only analgesia but also long-lasting hyperalgesia in rats. This suggests that tolerance to the analgesic effect of an opiate, especially heroin, could be in part the result of an actual sensitization of pronociceptive systems. Here, we show that both magnitude and duration of heroin-induced delayed hyperalgesia increase with intermittent heroin administrations, leading to an apparent decrease in the analgesic effectiveness of a given heroin dose. Our observation that a small dose of heroin which is ineffective for triggering a delayed hyperalgesia in non-heroin-treated rats induced an enhancement in pain sensitivity for several days after a series of heroin administrations is in agreement with the sensitization hypothesis. The effectiveness of the opioid receptor antagonist naloxone to precipitate hyperalgesia in rats that had recovered their pre-drug nociceptive value after single or repeated heroin administrations indicates that heroin-deprived rats were in a new biological state associated with a high level balance between opioid-dependent analgesic systems and pronociceptive systems. Because the NMDA receptor antagonist dizocilpine maleate (MK-801) prevented both heroin-induced long-lasting enhancement in pain sensitivity and naloxone-precipitated hyperalgesia, these findings further suggest that tolerance, sensitization, and one withdrawal symptom, hyperalgesia, are issued from a neuroadaptive process in which NMDA systems play a critical role.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U 259, Psychobiologie des Comportements Adaptatifs, Université Victor Ségalen Bordeaux 2, 33077 Bordeaux, France.
authors.forename: E
authors.initials: E
authors.lastname: Célèrier
authors.forename: J P
authors.initials: JP
authors.lastname: Laulin
authors.forename: J B
authors.initials: JB
authors.lastname: Corcuff
authors.forename: M
authors.initials: M
authors.lastname: Le Moal
authors.forename: G
authors.initials: G
authors.lastname: Simonnet
mesh_terms: D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D003932:Heroin / Q000008:administration & dosage / Q000009:adverse effects*; D006556:Heroin Dependence / Q000503:physiopathology*; D006930:Hyperalgesia / Q000139:chemically induced* / Q000503:physiopathology* / Q000517:prevention & control; D007279:Injections, Subcutaneous; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D009270:Naloxone; D016291:Dizocilpine Maleate; D003932:Heroin