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.

Figures

Fig. 1.

Effects of five intermittent heroin (1.25 mg/kg, s.c.) or saline administrations (black arrows) on nociceptive threshold in rats (n = 10–15 rats per group). A, Histograms represent the analgesic index (AUC) of each heroin administration evaluated on days 1, 4, 9, 17, and 25 and the analgesic effect of a low heroin dose (0.3 mg/kg, s.c.;white arrow) on day 37 in both the saline- and heroin-treated groups. B, Changes in basal nociceptive threshold determined by once-daily measurement of the nociceptive threshold. Mean pressure values for triggering vocalization (±SEM) were expressed in grams. *p < 0.05 and **p < 0.01 with Dunnett's test as compared with saline group. C, Effects of naloxone (1 mg/kg, s.c.;white arrow) on basal nociceptive threshold in saline- or heroin-treated rats. Naloxone was injected when animals had recovered their initial nociceptive threshold value after the first or fifth heroin administrations (days 4 and 33, respectively). The nociceptive threshold was measured 5 min after naloxone injection. Separate experiments were conducted for each naloxone test. Mean pressure values (±SEM) were expressed as a percentage of basal value. **p < 0.01 with Student's ttest as compared with pre-naloxone basal nociceptive value on day 4 or day 33.

Fig. 2.

A, Delayed effects of 12 once-daily heroin (0.3 mg/kg, s.c.) or saline administrations on basal nociceptive threshold in rats (n = 10 rats per group). Basal nociceptive threshold was determined daily before each heroin or saline administration and after the heroin treatment was stopped. Mean pressure values for triggering vocalization (±SEM) were expressed in grams. **p < 0.01 with Dunnett's test as compared with saline group. B, Effects of naloxone (1 mg/kg, s.c.; white arrow) on basal nociceptive threshold in saline- or heroin-treated rats. Naloxone was injected on day 25 when animals had recovered their pre-drug nociceptive threshold after the heroin treatment. The nociceptive threshold was measured 5 min after naloxone injection. Mean pressure values for triggering vocalization (±SEM) were expressed as a percentage of basal value. **p < 0.01 with Student's t test as compared with pre-naloxone basal nociceptive value.

Fig. 3.

A, Delayed effects of 12 once-daily heroin (2.5 mg/kg, s.c.) or saline administrations on basal nociceptive threshold in rats (black arrows; n = 9–10 rats per group). The basal nociceptive threshold was determined daily before each heroin or saline administration and after the heroin treatment was stopped. Delayed effects of a low heroin dose (0.2 mg/kg, s.c.; white arrow) on days 33 when animals had recovered their pre-drug nociceptive threshold after the heroin treatment. Mean pressure values for triggering vocalization (±SEM) were expressed in grams. **p < 0.01 with Dunnett's test as compared with basal nociceptive value on day 1. B, Effects of naloxone (1 mg/kg, s.c.; white arrow) on basal nociceptive threshold in saline- or heroin-treated rats. Naloxone was injected on day 29 when animals had recovered their pre-drug nociceptive threshold value after the heroin treatment. The nociceptive threshold was measured 5 min after naloxone injection. Mean pressure values for triggering vocalization (±SEM) were expressed as a percentage of basal value. **p < 0.01 with Student's t test as compared with pre-naloxone basal nociceptive value. C, D, Results obtained in experiment similar to A and B, respectively, in rats receiving 12 coadministrations of MK-801 (0.15 mg/kg, s.c.) and heroin (or saline). MK-801 was administered 30 min before each 2.5 mg/kg heroin administration.

Fig. 4.

Changes of the nociceptive threshold induced by 0.2 mg/kg heroin on days 1 and 13 before and after 12 once-daily 2.5 mg/kg heroin administrations (n = 9–15 rats per group). Mean pressure values (±SEM) were expressed in grams.Inset indicates comparison of areas under the curve. **p < 0.01 with Dunnett's test as compared with saline group.

Fig. 5.

Simplified schematic model illustrating the putative neuroadaptative continuum model linking sensitization, apparent tolerance, and hyperalgesic withdrawal symptom. Before the first exposure to heroin, an initial equilibrium (homeostasis) is associated with a low level balance between opioid-dependent analgesic systems (a) and NMDA-dependent pronociceptive systems (b) as indicated by the naloxone ineffectiveness in precipitating hyperalgesia. Dotted line represents the sum of the systems activity of a and b. Functioning levels of the latter are represented by the column height. Repeated heroin administrations induces a gradual decrease in the nociceptive threshold (Pronociceptive systems sensitization) leading to hyperalgesic state. This progressively shifts the unchanged analgesic response, giving the impression of less analgesia (apparent tolerance). After heroin treatment is stopped (Withdrawal), the return to pre-drug nociceptive threshold is not underlain by a deactivation of pronociceptive systems but is supported by an endogenous opioid system counteradaptation. The new equilibrium (allostasis) is associated with a high-level balance between opioid-dependent analgesic systems and NMDA-dependent pronociceptive systems leading to a long-term pain vulnerability.