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Antisense mapping of the MOR-1 opioid receptor clone: modulation of hyperphagia induced by DAMGO
L Leventhal1, L B Stevens, G C Rossi
1Department of Psychology, Queens College, City University of New York, New York, USA.
Abstract:
The mu opioid receptor mediates ingestive behavior: mu-selective agonists stimulate food intake and antagonists reduce intake in many ingestive situations. Antisense oligodeoxynucleotides directed against each of the four exons of the MOR-1 clone were equally effective in reducing spontaneous food intake and body weight in rats. However, antisense probes directed against only exon 1 or 4 of the MOR-1 clone reduced mu-mediated analgesia. The present study examined whether central administration of antisense probes directed against each of the four exons of the MOR-1 clone or a missense control altered hyperphagia elicited by the mu agonist DAMGO across a range of doses. Antisense probes directed against only exon 1 or 4 blocked hyperphagia at agonist doses of 0.5 and 1.0 microg; this pattern was identical to that observed for mu-mediated analgesia. A missense control failed to exert significant effects, which suggests specificity of antisense actions. The effective antisense probes failed to reduce hyperphagia at a higher (5 microg) agonist dose, a result consistent with limitations in down-regulation of receptor proteins by antisense. The mu antagonist beta-funaltrexamine produced a similar pattern of effects on mu-mediated hyperphagia. The selective actions of antisense probes directed against different exons of the MOR-1 clone in reducing hyperphagia induced by DAMGO suggest that multiple splice variants of the MOR-1 clone exist and raise the possibility of further opioid receptor subclassifications.
Insights
Antisense probes targeting specific MOR-1 gene exons reduced food intake and analgesia, suggesting distinct roles for mu opioid receptor variants in behavior and pain. This highlights potential for new opioid receptor subclassifications.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- The mu opioid receptor (MOR) is crucial for regulating ingestive behavior, with agonists stimulating and antagonists reducing food intake.
- Previous studies showed antisense oligodeoxynucleotides (ASOs) against MOR-1 exons reduced spontaneous food intake and body weight in rats.
- ASOs targeting only exon 1 or 4 of MOR-1 reduced mu-mediated analgesia, indicating exon-specific functions.
Purpose of the Study:
- To investigate if central administration of ASOs against MOR-1 exons affects hyperphagia induced by the mu agonist DAMGO.
- To determine the specificity of antisense actions using a missense control.
Main Methods:
- Rats received central administration of ASOs targeting each of the four MOR-1 exons or a missense control.
- Hyperphagia was elicited by various doses of the mu agonist DAMGO.
- The effects of ASOs on DAMGO-induced hyperphagia and mu-mediated analgesia were assessed.
Main Results:
- ASOs targeting only exon 1 or 4 blocked DAMGO-induced hyperphagia at lower agonist doses (0.5 and 1.0 microg).
- This pattern mirrored the effects on mu-mediated analgesia, suggesting shared regulatory mechanisms.
- A missense control did not significantly affect hyperphagia, confirming the specificity of antisense probes.
- Effective ASOs failed to reduce hyperphagia at a higher DAMGO dose (5 microg), indicating limitations in antisense-mediated receptor downregulation.
- The mu antagonist beta-funaltrexamine produced similar effects on mu-mediated hyperphagia.
Conclusions:
- Selective actions of ASOs against different MOR-1 exons suggest the existence of multiple MOR-1 splice variants.
- These findings raise the possibility of further subclassifications within the mu opioid receptor family.
- Differential targeting of MOR-1 variants could offer novel therapeutic strategies for appetite and pain modulation.