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Antisense mapping of opioid receptor clones: effects upon 2-deoxy-D-glucose-induced hyperphagia
K Burdick1, W Z Yu, A Ragnauth
1Neuropsychology Doctoral Sub-Program, Queens College, CUNY, Flushing, NY 11367, USA.
Abstract:
Antisense oligodeoxynucleotides (AS ODNs) directed against exons 1 and 2 of the MOR-1 clone significantly and markedly reduced (81-93%) hyperphagia induced by the anti-metabolic glucose analogue, 2-deoxy-d-glucose (2DG) across a 4 h time course. AS ODNs directed against exons 3 or 4 of the MOR-1 clone had a more limited (1-2 h) duration of action upon 2DG-induced hyperphagia. 2DG-induced hyperphagia was significantly reduced by AS ODNs directed against exon 2 (44-51%), but not exons 1 or 3 of the KOR-1 clone across a 4 h time course. Whereas an AS ODN probe directed against the KOR3/ORL-1 clone produced small (36%), but significant reductions in 2DG-induced hyperphagia, an AS ODN probe directed against the DOR-1 clone was ineffective. These data provide further converging evidence for the roles of primarily mu, but also kappa1 and kappa3 opioid receptors in mediating the hyperphagic effects of glucoprivation.
Insights
Antisense oligodeoxynucleotides targeting mu-opioid receptors significantly reduced 2-deoxy-d-glucose (2DG)-induced hyperphagia. Kappa opioid receptors also play a role in this feeding response.
Area of Science:
- Neuroscience
- Endocrinology
- Pharmacology
Background:
- Glucoprivation, a state of low glucose availability, triggers feeding behaviors.
- Opioid receptors, particularly mu-opioid receptors (MOR), are implicated in regulating appetite and energy balance.
Purpose of the Study:
- To investigate the specific roles of different opioid receptor subtypes (MOR, KOR, DOR) in mediating hyperphagia induced by glucoprivation.
- To determine the efficacy and duration of antisense oligodeoxynucleotides (AS ODNs) targeting various opioid receptor clones in reducing 2-deoxy-d-glucose (2DG)-induced feeding.
Main Methods:
- Administration of AS ODNs targeting specific exons of MOR-1, KOR-1, KOR3/ORL-1, and DOR-1 clones in rodents.
- Induction of hyperphagia using the anti-metabolic glucose analogue, 2-deoxy-d-glucose (2DG).
- Quantification of feeding responses and assessment of AS ODN efficacy over a 4-hour time course.
Main Results:
- AS ODNs targeting MOR-1 exons 1 and 2 markedly reduced 2DG-induced hyperphagia (81-93%) for up to 4 hours.
- AS ODNs targeting KOR-1 exon 2 significantly reduced hyperphagia (44-51%), while KOR3/ORL-1 showed a smaller reduction (36%).
- AS ODNs targeting DOR-1 were ineffective in altering 2DG-induced hyperphagia.
Conclusions:
- These findings provide strong evidence for the critical role of mu-opioid receptors in mediating 2DG-induced hyperphagia.
- Kappa-1 and kappa-3 opioid receptors also contribute to glucoprivic feeding, albeit to a lesser extent than mu-opioid receptors.
- AS ODN technology targeting specific opioid receptor subtypes offers a potential strategy for modulating feeding behaviors related to energy homeostasis.