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 heroininduced 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.

Tolerance, opioid-induced allodynia and withdrawal associated allodynia in infant and young rats

“…This is similar to other reports that as few as two low dose injections of heroin or 4 bolus doses of fentanyl can induce mechanical hyperalgesia , Celerier et al, 2000. The duration of hyperalgesia has been reported to lengthen with each exposure to heroin (Celerier et al, 2001). This may at least partly explain the prolonged mechanical allodynia in young rats following cessation of IM.…”

“…This study did not differentiate whether the prolonged allodynia is a result of 1) a delay in the maturation of paw withdrawal thresholds or 2) the presence of prolonged withdrawalassociated allodynia. Hypersensitivity long into the abstinent period has been previously reported in adult rats following heroin or fentanyl (Laulin et al, 1998, Celerier et al, 2000, Celerier et al, 2001. At the neural level, prolonged excitation persist long after abstinence in dorsal root ganglion cultures exposed to chronic morphine (Crain and Shen, 1995).…”

Chronic Morphine Selectively Impairs Cued Fear Extinction in Rats: Implications for Anxiety Disorders Associated with Opiate Use

“…This induction of hyperalgesia by chronic opiate treatment is a timedependent process (Celerier et al, 2001;Li et al, 2001). Our present results showed that chronic morphine did not produce a significant difference in nociceptive response measurements between the morphine-treated rats and the normal saline rats (Figure 3a and b).…”

Effects of sevoflurane on carrageenan- and fentanyl-induced pain hypersensitivity in Sprague-Dawley rats

“…In the rat model for such experiments, this pain vulnerability developed after the exposure to high doses of opioids could be revealed by naloxone administration, whereas NT did eventually normalize. 13,32 In the present study, sevoflurane demonstrated potentially beneficial properties that could decrease naloxone-induced hyperalgesia.…”

“…6,12,19,31 Further evidence of this phenomenon originates from experimental studies that report hyperalgesia lasting for several days after heroin or fentanyl administration. 32,33 The concept of general balanced anesthesia is defined by the co-administration of several pharmacological agents, so as to enhance their beneficial effects while reducing the side effects of individual drugs administered in high doses. 34 Clinical studies have reported that the reduction of intraoperative opioid doses is associated with diminished postoperative pain and reduced morphine consumption.…”