Repeated Heroin Administration: A Sensitization Process
DISCUSSION
The first result of this study is that intermittent administrations of the same dose of heroin induced not only an analgesic effect but also a long-lasting enhancement in pain sensitivity (hyperalgesia), as observed with the progressive emergence of a delayed decrease of the nociceptive threshold for several days. This hyperalgesia cannot be explained by an excess of nociceptive inputs induced by behavioral testing associated with heroin administration because we reported previously that long-lasting hyperalgesia is also observed in opiate-treated rats unexposed to repeated nociceptive stimuli on the day of opiate administration (Laulin et al., 1998; Ce ´le `rier et al., 2000). This phenomenon appears an actual sensitization of pronociceptive systems because both magnitude and duration of hyperalgesia increased as a function of heroin administrations. Indeed, we observed that the first 1.25 mg/kg heroin administration induced moderate hyperalgesia for 2 d, whereas the fifth injection of the same heroin dose was followed by a larger hyperalgesia for 6 d. Our study also shows that repeated 12 once-daily subcutaneous heroin injections induced a gradual lowering of the nociceptive threshold that progressively disappeared after the cessation of the heroin treatment. Thermal hyperalgesia has also been reported 48 hr after cessation of a series of 8 once-daily intrathecal injections of morphine (Mao et al., 1994).
Our observation that the administration of a small heroin dose (0.2 or 0.3 mg/kg), which was ineffective in inducing a delayed hyperalgesia after the first exposure in rats, triggered substantial delayed hyperalgesia after a series of intermittent or once-daily heroin administrations is in agreement with the sensitization hypothesis. Considered as a whole, these results clearly indicate that a repeated heroin administration schedule induced a sensitization to heroin-induced delayed hyperalgesia.
The second result of this study is that pain hypersensitivity progressively disappeared in heroin-treated rats after the cessation of heroin administrations, as demonstrated by the slow return of the nociceptive threshold to the pre-drug value. Interestingly, the larger the decrease of the nociceptive threshold, the larger was the delay to return to basal pain sensitivity. Two types of processes might account for this phenomenon. The first one would be a progressive deactivation of pronociceptive systems according to a mere homeostatic process. The second one would be a sustained and prolonged activity of the pronociceptive systems progressively opposed by an active and opposite counteradaptation that is isodirectional to the first effect of the opiate (Poulos and Cappell, 1991; Ramsay and Woods, 1997), i.e., pain inhibition by endogenous analgesic systems (Fig. 5). Although a progressive deactivation of pronociceptive systems after the cessation of heroin administrations could not be excluded totally, our results strongly suggest a critical role for the second process. This is supported by the effectiveness of naloxone in precipitating hyperalgesia in rats that had recovered their pre-drug nociceptive threshold value after stopping heroin administration. Although the effectivenes of naloxone in precipitating hyperalgesia was only slightly increased between the first and fifth heroin injections (32 and 48% decrease of the nociceptive threshold, respectively) in the intermittent heroin injection schedule, our observation that the naloxone-precipitated hyperalgesia was maintained for 2 months after a series of 12 daily heroin administrations had ended (35% decrease of the nociceptive threshold) provides evidence that compensatory mechanisms permitting maintenance of the pre-drug nociceptive threshold value were sustained for a long time. Because an opioid receptor antagonist, which was ineffective in control heroin naive rats, induced a pharmacological effect such as hyperalgesia, this means either that opioid receptors were stimulated by a compensatory increase of endogenous opioid ligands or that signaling activity of opioid receptors is enhanced.
Indeed, it has been reported that opioid agonist stimulation results in a gradual conversion of the m opioid receptor into a sensitized or constitutively active state (Wang et al., 1994; Bilsky et al., 1996) and upregulation of the cAMP pathway (Nestler, 1992). Although these three mechanisms may account for the naloxone-precipitated hyperalgesia, the unmodified analgesic effects of heroin in this model of discontinuous administration favors the hypothesis of an increase of endogenous opioid ligands.
Studies are in progress in our laboratory to identify the nature of endogenous opioids that could be involved in this adaptive process, permitting a return to basal nociceptive threshold. Taken together, these studies suggest that heroin-deprived animals were, for a very long-time, in a new biological state associated with a high-level balance between opioid-dependent analgesic systems and pronociceptive systems that mask one another (Fig. 5). This is in agreement with the compensatory response hypothesis (Wise, 1988; Schulteis and Koob, 1996; Robinson and Berridge, 2000), especially the opponent process theory (Solomon, 1980).
The third result of our study is that, unlike sensitization of heroin-induced hyperalgesia observed after repeated administration, a change in heroin-induced analgesia was never observed.
As reported earlier (Laulin et al., 1999), we observed that both time course and AUC related to the analgesic effect of heroin were unchanged when the opiate was injected during the hyperalgesic phase induced by heroin. During the hyperalgesic period, the shift of the nociceptive threshold is actually what produced the impression of less analgesia, i.e., apparent tolerance. Moreover, this study showed that the analgesic effect of heroin was also unchanged when heroin is administered in heroin-treated animals that recovered their pre-drug nociceptive threshold value after cessation of heroin administrations, and it is in agreement with some studies showing that intermittent exposure may lead to sensitization of a drug effect, whereas continuous exposure to a drug may lead to tolerance of the same drug effect (Post, 1980).
This could explain why controlled clinical studies report that the dose of opiates that is required in chronic pain patients to alleviate pain (intermittent exposure) may remain constant for years on end (Twycross and McQuay, 1989; Foley, 1991; Portenoy, 1996). Taken together, these data indicate that the increases of the opiate doses that are sometimes required to alleviate pain in suffering patients are caused either by disease progression leading to aggravation of pain, as suggested previously (Collin et al., 1993; Colpaert, 1996), or by an excessive enhancement of pain sensitivity induced by repeated opiate administration, as observed in this study. In this respect, apparent tolerance to the opiate analgesic effect observed in intermittent heroin-treated rats appears as a by-product resulting from a pain sensitization process.
The relationships between apparent tolerance, pain sensitization, and naloxone-precipitated hyperalgesia observed in intermittent heroin-treated rats lead to the assumption that if the sensitization process was prevented before the drug effect was initiated, apparent tolerance, pain sensitization, and naloxone-precipitated hyperalgesia could not be expressed. Numerous studies demonstrated that the NMDA receptor antagonist may prevent the expression of sensitization processes (Stewart and Badiani, 1993), especially pain sensitization leading to hyperalgesia, allodynia, and spontaneous pain (Haley and Wilcox, 1992; Mao et al., 1995; Coderre and Katz, 1997). Of note is the observation that m-opioid receptor stimulation triggers the activation of NMDA receptors by reducing Mg21 blocking via intracellular protein kinase C (PKC) activation (Chen and Huang, 1991, 1992). It has been suggested that the subsequent increase of intracellular Ca21 concentration further stimulates PKC activity leading to a lasting enhancement of glutamate synaptic efficiency in a positive feedback (Mao et al., 1995; Coderre and Katz, 1997).
The present study shows that the NMDA receptor antagonist MK-801, when administered just before heroin, not only precluded sustained heroin-induced delayed hyperalgesia as described previously (Laulin et al., 1998, 1999) but also prevented the effectiveness of a small heroin dose to induce a sustained hyperalgesia in heroin-deprived rats, a critical criterion for sensitization. No apparent tolerance was observed. Moreover, MK-801 also prevented naloxone effectiveness in precipitating hyperalgesia in heroin-deprived rats that had recovered their pre-drug nociceptive threshold value. This indicates that naloxone-precipitated hyperalgesia is the result of the sharp breakdown of an equilibrium between opioid-dependent analgesic systems and NMDA-dependent pronociceptive systems. Because NMDA receptor antagonists can prevent the development of sensitization and long-term potentiation (Kullmann and Siegelbaum, 1995; Hudspith, 1997), our results lead to the hypothesis that pain sensitization and some signs of withdrawal such as hyperalgesia are issued from a neuroadaptive continuum triggered by opioid receptor stimulation in which NMDA-dependent pronociceptive systems play a critical role.
Source: J Neurosci. 2001 Jun 1;21(11):4074-80.
Evelyne Ce ´le ` rier, Jean-Paul Laulin, Jean-Benoı ˆt Corcuff, Michel Le Moal, and Guy Simonnet
Institut National de la Santé et de la Recherche Médicale U 259, Psychobiologie des Comportements Adaptatifs, Université Victor Ségalen Bordeaux 2, 33077 Bordeaux, France.
