Test-specific effects of the 5-HT reuptake inhibitors alaproclate and zimelidine on pain sensitivity and morphine analgesia

Abstract

The effects of the specific 5-HT uptake inhibitors alaproclate and zimelidine, the 5-HT releasing compound p-chloroamphetamine (PCA) and the specific NA uptake inhibitor desipramine on pain sensitivity were examined in male rats using the hot-plate and tail-flick methods. The effects of alaproclate and zimelidine on 5-HT uptake mechanisms in the hypothalamus and spinal cord were also studied. Alaproclate, zimelidine, PCA and desipramine produced hypoalgesia in the hot-plate but not in the tail-flick test. Naloxone (1 mg/kg) failed to block the hypoalgesia produced by alaproclate and PCA in the hot-plate test. Zimelidine but not desipramine pretreatment blocked the analgetic action of PCA in the hot-plate test. Alaproclate significantly enhanced morphine analgesia in the hot-plate test but did not affect morphine analgesia in the tail-flick test. In contrast, zimelidine tended to enhance and significantly prolonged morphine analgesia in the tail-flick test but did not affect morphine analgesia in the hot-plate test. Zimelidine inhibited 5-HT uptake with equal potency in the hypothalamus and spinal cord, while alaproclate produced a greater inhibition of 5-HT uptake in the hypothalamus. These findings show test-specific effects after enhancement of central 5-HT neurotransmission. It is suggested that various aspects of pain sensitivity and morphine analgesia may involve different 5-HT pathways in the brain and spinal cord. Moreover, 5-HT pathways in the forebrain may mediate analgesia of a non-opiate type.

Alaproclate, a new selective 5-HT uptake inhibitor with therapeutic potential in depression and senile dementia

“…Its low inhibitory potency in the spinal cord suggests that alaprocalte may have only slight effect on 5-HT uptake in the descending 5-HT systems. Behavioural studies in rats and mice also indicate that alaproclate produces only weak inhibition of 5-HT uptake in the spinal cord (Ogren and Holm, 1980). The regional differences in 5-HT uptake inhibition produced by alaproclate could possibly be accounted for by the regional distribution of the compound.…”

The involvement of the opioidergic system in the antinociceptive mechanism of action of antidepressant compounds

“…Botney and Fields (1983) showed a potentiation of morphine antinociception by amitriptyline but produced no effect alone. Ogren and Hölm (1980) were unable to identify any intrinsic antinociceptive activity of antidepressants. Biegon and Samuel (1979, 1980) demonstrated the ability of tricyclic antidepressants to bind to opioid receptors suggesting that antidepressants may have weak opioid‐like actions.…”

Antinociceptive, antiedematogenic and antiangiogenic effects of benzaldehyde semicarbazone

“…On the other hand, the nociceptive response in the hot-plate model results from immediate and direct activation of nociceptive afferent fibers by temperatures higher than their activation threshold (Caterina et al, 1997). An antinociceptive effect in the hot-plate model is usually observed after treatment of the animals with centrally acting drugs such as opioid analgesics (Hammond and Proudfit, 1980), 5-hydroxytryptamine (Ogren and Holm, 1980) and norepinephrine (Tura and Tura, 1990) uptake inhibitors and α2-adrenoceptor agonists (Takano and Yaksh, 1992), but not after treatment with drugs that inhibit the synthesis or action of inflammatory mediators (Engelhardt et al, 1995;Correa et al, 1996;Fantetti et al, 1999). The inhibition of carrageenan-induced allodynia but not the nociceptive response in the hot-plate model also gives support for a more marked peripheral action to explain BS antinociceptive effect.…”