Sous-types de récepteurs opiacés et sigma dans le système nerveux : distribution dans le système nerveux centra,l rôle fonctionnel et transport axonal
(1995)
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- Authors
- Supervisors
- Maloteaux, Jean-Marie
- Abstract
- This is a work of fundamental research in the field of neuropharmacology, especially neuroreceptors. Our interest for the pharmacotherapy of pain has lead us to the study of opiate receptors. Indeed, morphine and opiates keep a key role in medicine. <BR> This work will be divided in two parts: the first one concerning opiate receptors, the second one concerning sigma receptors, which are, now, no more referred to as opiate receptors. In each part, personal experimental results will b presented after a review of the subject. The multiplicity of experimental methods was required by the multiple subtypes of opiate receptors and their various functions. <BR> The regional distribution of receptor subtypes is important to precise, since abnormalities of neurotransmitters systems might be involved in some pathological conditions. We have characterized systems might be involved in some pathological conditions. We have characterized µ and κ opiate receptors in human brain, and studied their regional distribution, using binding methods. Bmax value for µ opiate receptors in human frontal cortex was about 40 fmol/mg of tissue, which was in the same range as previously reported. Bmax value for κ opiate receptors in human frontal cortex was lower than for µ opiate receptors: between 8 and 15 fmol/mg of tissue. Such a specific measure has not been previously reported. Regional distribution of ù opiate receptors was comparable when studied with [3H]lofentanil of with [3H]sufentanil as ligands, and showed an enrichment in the frontal and anterior temporal regions, with an anterior-posterior decreasing gradient. Very high levels of µ opiate receptors were also found in the thalamus. The regional distribution of κ opiate receptors was comparable when studied with [H3]brelazocine or with [3H]CI977. Though a more diffuse distribution in the cerebral cortex, there was also an anterior enrichment for κ opiate receptors. It is interesting to notice that the regions mainly involved in sensory (thalamus) and affective (frontal and anterior temporal cortex) process are the most enriched in opiate receptors. The regional experiments is compatible with the regional distribution of [11C]diprenorphine, suited in vivo, by the mean of emission positron tomography, and which also showed a frontal enrichment. The subcellular distribution of µ opiate receptors has been studied with [3H]lofentanil and shows an enrichment in the microsomal fraction. <BR> Complex interactions between opiate and dopaminergic systems have been reported. In the striatum, κ agonists clearly modulate the release of dopamine, possibly by a presynaptic mechanism. The aim of our experiments was to precise the anatomical relations between κ opiate receptors and the dopaminergic neurons of the nigrostriatal pathways, in rat and in human. In the model of rats, lesionned with 6-hydrowydopamine, we could observe a decrease of about 40% if the amount of κ opiate receptors in the striatum, suggesting that some if these sites are located on nigrostriatal dopaminergic terminals. However, since this decrease was lee pronounced than that of dopamine uptake sites, it is likely that some κ opiate receptors might be located in other cell types. <BR> We have measured κ opiate receptors in samples of human putamen and human frontal cortex of control subjects and from patients with supranuclar palsy and with Parkinson’s disease, which is a human model of nigrostriatal degeneration. Data of experiments performed in human brain are different from those obtained on animals. Indeed, there was no decrease of the among of κ opiate receptors in any region of patients, when compared to control subjects. Therefore, the hypothesis of a presynaptic localization of κ opiate receptors on nigrostrialal dopaminergic neurons was not confirmed in human brain. It should be remembered that in Parkinson’s disease, there is always a strong nigrostriatal dopaminergic degeneration, and all markers if dopaminergic neurons are always severely decreased: dopamine itself, tyrosine hydroxylase, dopamine uptake sites or neurotensin receptors. Therefore we conclude that, in human, κ opiate receptors are preferentially located on other neurons than nigrostriatal dopaminergic neurons. The modulations of dopamine release in the striatum might be differently modulated by opiate receptors in human and in rat. […]
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Citations
Jeanjean, A. P. (1995). Sous-types de récepteurs opiacés et sigma dans le système nerveux : distribution dans le système nerveux centra,l rôle fonctionnel et transport axonal. https://hdl.handle.net/2078.5/111150