Antisense oligodeoxynucleotides against the MOR-1 clone alter weight and ingestive responses in rats

MOR-1 encodes a mu receptor. In an effort to establish the relationship of this cloned opioid receptor with ingestive behavior and analgesia in rats, the present study examined the actions of four antisense oligodeoxynucleotides aimed at exons 1 (AS1), 2 (AS2), 3 (AS3) and 4 (AS4) of the MOR-1 clone, as well as a mismatch antisense sequence (MS1). Rats were administered intracerebroventricular injections (10 micrograms/2 microliters) of each of the oligodeoxynucleotides on days 1, 3 and 5. Body weight and spontaneous food and water intake were monitored daily. In addition, 2-deoxy-D-glucose (2DG)-induced hyperphagia, central Angiotensin II (ANG-II) induced hyperdipsia and central morphine analgesia were examined 24 h following the last antisense injection. AS1, AS2, AS3 and AS4 each significantly reduced body weight (7-17 g), food intake (8-13 g) and water intake (11-23 ml), while the vehicle or MS1 conditions significantly increased weight (9-20 g) and produced smaller reductions (2-4 g) in food intake. None of the AS probes altered the magnitude of either 2DG-induced hyperphagia or ANG-II-induced hyperdipsia. Central morphine analgesia was reduced by pretreatment with AS1 and AS4, but not AS2, AS3 or MS1. The sensitivity of general feeding to all four exons suggest that the receptor responsible for this action is encoded by the MOR-1 clone. The differences between feeding and morphine analgesia raise the possibility that these two actions are mediated through different mu receptor subtypes. Our results also demonstrate the viability of the in vivo antisense technique in modulating opioid-mediated ingestive responses.