Sub-anorectic doses of SR141716A and naloxone synergistically suppress appetite in rats: an observational analysis

Niki Rust, Benjamin J. Whalley, Claire M. Williams. University of Reading, Reading, Berkshire, United Kingdom.

Endogenous opioid and cannabinoid ligands play a significant role in appetite regulation with both cannabinoid CB1 and opioid antagonists reducing feeding (Williams et al., 2002). Amassed evidence also shows that CB1 agonists and antagonists affect incentive components of feeding, whilst opioid systems are more firmly linked to feeding maintenance processes (Kirkham, 1990; Gallate et al., 1999). Interestingly, it has been shown that a combined dose of CB1 (SR141716) plus opioid (naloxone) antagonists works synergistically, even at sub-anorectic doses, to produce greater feeding suppression than either drug alone (Kirkham et al., 2001). This strongly suggests a functional interaction between endogenous cannabinoid and opioid systems in feeding regulation although no extant work has investigated the precise behavioural alterations underlying these effects.

Consequently, we used detailed observational analyses to determine behavioural changes produced by a combined dose of 1 mg kg-1 SR141716 plus 1 mg kg-1 naloxone (termed ‘SR-NX’) (Williams et al., 2001); in particular, to establish the specific components of feeding affected by these compounds. Two groups (n=6) of adult male Lister-hooded rats (outbred; 350-450g) received a s.c. injection of either vehicle or SR-NX. Behaviour (eating, drinking, rearing, grooming, locomotion or inactivity) was monitored for 1 hour to give information on the latency, temporal distribution, duration and frequency of each behavioural category. Significance was calculated via t-tests performed on all comparisons vs. vehicle. In line with previous findings, SR-NX significantly suppressed food intake throughout the experiment (33%; P<0.05). Moreover the frequency and the length of meal bouts were decreased when compared with vehicle. Together, these changes led to an overall reduction in time spent involved in feeding-related activities (12%; P<0.01). Changes in other behavioural categories were also apparent with SR-NX, significantly reducing time spent drinking and rearing but increasing time spent inactive (25%, P<0.01; 77%, P<0.005; 677%, P<0.001 respectively).

These novel results are the first to show that sub-anorectic doses of SR-NX produce specific modifications of normal feeding regulation processes rather than resulting from non-specific actions such as induction of stereotypy. These actions of SR-NX are consistent with mutually dependent actions of cannabinoid and opioid systems in feeding maintenance and their further investigation may have substantial benefits for the understanding and management of eating and body weight regulation disorders.

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