NeuroscienceThe effect of a paracetamol and morphine combination on dynorphin A levels in the rat brain4
Introduction
Many reports suggest that PARA exerts its analgesic activity both at peripheral and central levels in animals and humans through an inhibitory action on the synthesis of prostaglandins with the pre-eminent action of cyclo-oxygenase 1 [1]. However, increasing evidence suggests that the inhibition of cyclo-oxygenase may not be solely responsible for the central analgesic effect of PARA and NSAIDs [2], [3]. It has been suggested that a number of neurotransmitter systems may be involved in the central analgesic effect of NSAIDs and PARA; in particular, serotonergic pathways may play a pivotal role in the central antinociceptive mechanism of NSAIDs [4], [5] and PARA [6], [7]. In particular, paracetamol possesses a central antinociceptive effect that is accompanied by an increase in brain serotonin content in cortical membranes. On the other hand, it has been shown that morphine stimulates serotonin release via a supraspinal action [8], [9], the effect being regionally selective [10].
Pretreatment with naloxone abolished the antinociceptive effect and the increase in 5-hydroxytryptamine (5-HT) concentration induced by PARA or morphine in cortical membranes [11]. The possibility that morphine and PARA may involve interconnected pathways in their mechanism of action prompted us to investigate the effect of a combination of inactive doses of the two drugs on nociception in rats. Our previous data demonstrated that inactive doses of PARA and morphine, given in combination, have an antinociceptive activity that is associated with an increase in 5-HT levels in the cerebral cortex. Both the antinociceptive and the biochemical effects were prevented by naloxone [12].
Morphine exerts its analgesic effect through a direct activation of central opioid receptors in the CNS, namely μ and, to a lesser extent, κ and δ, and an indirect action influencing the release of opioid peptides or other neurotransmitters [13]. Few reports are available on the effect of an acute treatment with morphine, but it is documented that chronic treatment decreases methionine-enkephalin, pro-enkephalin, and β-endorphin in some brain areas [14]. In several CNS areas, peptides were unaffected by an acute injection of morphine, although DYN peptides were decreased in the brainstem and hippocampus (DYN A and DYN B).
Dynorphins, a family of endogenous opioids related to the opioid precursor prodynorphin, are potential modulatory peptides [15] having a role in opiate analgesia [16], [17]. DYN (1–13), which is known to be a selective endogenous ligand for κ-receptors, is widely distributed in the CNS, peripheral nervous system (PNS), and pituitary gland tissues [18]. The stimulation of κ-receptors in the CNS seems to produce analgesia [19]. On the other hand, DYN (1–13) attenuated opiate analgesia when i.c.v. injected in rats naive to morphine [20]. The role of DYN in analgesia is controversial; while Tseng and co-workers found that i.c.v. injection of bremazocine, a κ-receptor agonist, induced the release of DYN for the production of antinociception [21], [22], other authors hypothesised that DYN is released in response to certain i.c.v. agonists, including morphine, for the production of antianalgesia, and proposed a mediator role for DYN in a descending antianalgesic system [23].
Our decision to determine the DYN (1–13) level in the cortex was suggested by data indicating that acute and chronic pain changes the levels of the peptide in this and other areas of the brain [24], as does morphine treatment [25]. We focused our attention on the cerebral cortex, because it is a major site of projections from the ventral thalamus and takes part in one of the multiple neural systems responsible for pain processing [26]. Furthermore, opioid receptor subtypes are widely distributed in the cerebral cortex where they modulate noxious stimuli [27]. Finally, in our previous experiments, we demonstrated that a full antinociceptive dose of PARA reduced DYN A levels only in the cerebral cortex among the several areas investigated.1
The aim of this work was to investigate the possible involvement of an opioidergic mechanism in the antinociceptive effect of the combination of inactive doses of PARA and morphine; this was explored by studying the influence of the pretreatment of naloxone or MR 2266, [(−)-2-(3 furylmethyl)-normetazocine], a κ-opioid receptor antagonist, on the drug combination. To elucidate whether the analgesic effect of the combination may be correlated with changes in the opioid levels, we chose to evaluate DYN A (1–13) levels in the frontal and temporal–parietal cortex in the rat brain and the effect of a pretreatment with the same antagonists thereon. We also evaluated the effect of an analgesic dose of PARA or morphine alone on DYN A levels in the same areas.
Section snippets
Animals
Adult male Wistar rats (Harlan-Nossan) weighing 180–190 g at the beginning of the experiments, were housed in Plexiglas cages, four per cage, with free access to food and water, and were maintained on a 12-hr dark/light cycle (light on at 7 a.m.) under controlled environmental conditions (temperature 22 ± 1°; humidity 60%). The ethical guidelines for investigation of experimental pain in conscious animals were followed in all tests, and all the procedures were carried out according to the EEC
Results
The antinociceptive effect of the PARA and morphine combination was completely prevented by pretreatment with naloxone (1 mg/kg i.p.) or MR 2266 (5 mg/kg i.p.) (Table 1); the factorial analysis showed a negative interaction [F(1–28) = 6.8; P < 0.01]; [F(1–28) = 6.2; P < 0.01]. The two opioid antagonists alone did not affect the % MPE values; moreover, neither PARA (100 mg/kg) alone nor a single dose of morphine (3 mg/kg) was able to modify the levels of ir-DYN A in the frontal or
Discussion
The combination of inactive doses of PARA and MORP provoked an antinociceptive effect in the hot plate test that was prevented by pretreatment with naloxone or MR 2266. This result agrees with the suggestion that the analgesic action of NSAIDs and PARA is carried out, at least in part, through the opioidergic system [32]. To confirm the possible involvement of an opioidergic mechanism in the antinociceptive effect of the paracetamol and morphine combination, we evaluated the levels of DYN A in
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Abbreviations: NSAIDs, non-steroidal anti-inflammatory drugs; DYN, dynorphin; PARA, paracetamol; and ir-DYN, immunoreactive dynorphin.