Effects of pre- or postoperative morphine and of preoperative ketamine in experimental surgery in rats, evaluated by pain scoring and c-fos expression

Abstract

Since Wall (1988) hypothesised a beneficial post surgical effect of preoperative analgesic treatment (so-called pre-emptive analgesic treatment) as a supplement to postoperative analgesic treatment, the concept has been subject to many scientific debates. According to the hypothesis, applying analgesics before the nociceptive stimulus is beneficial due to reduced wind-up and reduced central sensitisation resulting in diminished risk of postoperative hyperalgesia and allodynia (Woolf and Chong, 1993).

 The scientific literature provides conflicting evidence for this theory. Beneficial effect of preemptive analgesic treatment has been reported after pre-emptive treatment with local analgesics, opioids and NSAID´s compared with placebo (Woolf and Chong, 1993). Some clinical settings have showed beneficial analgesic effect of preemptive analgesia, when the same pre-emptive and postoperative treatments with lidocaine (Ejlersen et al., 1992; Doyle and Bowler, 1998) or opioids (Katz et al., 1992) were compared. However, Dahl et al. (1992) and Elhakim et al. (1995) did not obtained supportive results in their clinical studies.

In the majority of studies using animal models addressing this concept, the nociceptive stimulus has been obtained by injection of irritating chemicals, in particular formalin. When somatic tissue is damaged or irritated, nociceptive receptors are activated by peripheral release of extracellular inflammatory mediators. The activated receptors lead the signal to the synapses in the dorsal horn of the spinal cord as a 2-phased signal. In the acute first phase, nociceptive stimuli are mediated centrally through Aä fibres fibres. During the slower and long-lasting second phase, the nociceptive stimuli are mediated mainly through C-fibres (Cross et al., 1994). The release of extracellular inflammatory mediators increases the peripheral excitability, which leads to hyperalgesia (Woolf, 1995). Repetitive peripheral nociceptive impulses mediated through C-fibres result in an increased central excitability of dorsal appears to be in part mediated through N-methylhorn neurones. This state is called wind-up and appears to be in part mediated through N-methyl- D-aspartate (NMDA) receptors on dorsal horn secondary nociceptive neurones. Transmission of multiple slow stimuli leads to release of glutamate, which removes the Mg++-block in the NMDA receptor and allows substantial Ca++-inflow (Urban et al., 1994). NMDA receptor antagonists bind to the same site as Mg++ and prevents Ca++- inflow (Hirota and Lambert, 1996; Kress, 1997). NMDA-receptor antagonists can prevent wind-up but not the initial responses of the neurones, whereas the reverse is true for opioids (Chapman and Dickenson, 1992). NMDA-antagonists have no effect on pain of the acute first phase, but may act synergistic to the analgesic effect of opioids (Chapman and Dickenson, 1992; Honoré et al., 1996).

Only few studies deal with a postoperative experimental model in animals and those available are conflicting. Brennan et al. (1996) developed an elegant postoperative model in rats with surgical intervention on the plantar surface of the hind foot. In this study a relationship was found between behavioural pain observation scores and mechanical hyperalgesia. Ovariohysterectomized rats have also been used as animal models of postoperative pain (Lascelles et al. 1995).

A commonly used method of determining the nociceptive activity caused by a peripheral stimulus is to identify and quantify the nuclear protein Fos expressed in secondary nociceptive neurones in the spinal cord. c-fos is an immediate early gene (IEG), that encodes for Fos. IEG’s are rapidly and transiently induced in neuronal cells within minutes of extracellular stimulation (Sheng and Greenberg, 1990). The c-fos mRNA accumulates, and reaches its peak after 30 to 40 minutes. The Fos level peaks approximately two hours after induction of c-fos (Harris, 1998). Since Hunt (1987) reported, that peripheral inflammation induced c-fos in neurones in the dorsal horn of the spinal cord, many studies have shown the relationship between nociception and cfos expression.

The aim of the present investigation was to study the effect of pre-emptive versus postoperative opioid analgesic treatment by use of the surgical model of Brennan et al. (1996) and combine the pre-emptive and postoperative opioid treatment with pre-emptive ketamine. The effects were quantified by stereological estimation of the number of dorsal horn neurones expressing c-fos and pain scoring from the operated hind foot.