title: Central functional response to the novel peptide cannabinoid, hemopressin.
abstract: Hemopressin is the first peptide ligand to be described for the CB₁ cannabinoid receptor. Hemopressin acts as an inverse agonist in vivo and can cross the blood-brain barrier to both inhibit appetite and induce antinociception. Despite being highly effective, synthetic CB₁ inverse agonists are limited therapeutically due to unwanted, over dampening of central reward pathways. However, hemopressin appears to have its effect on appetite by affecting satiety rather than reward, suggesting an alternative mode of action which might avoid adverse side effects. Here, to resolve the neuronal circuitry mediating hemopressin's actions, we have combined blood-oxygen-level-dependent, pharmacological-challenge magnetic resonance imaging with c-Fos functional activity mapping to compare brain regions responsive to systemic administration of hemopressin and the synthetic CB₁ inverse agonist, AM251. Using these complementary methods, we demonstrate that hemopressin activates distinct neuronal substrates within the brain, focused mainly on the feeding-related circuits of the mediobasal hypothalamus and in nociceptive regions of the periaqueductal grey (PAG) and dorsal raphe (DR). In contrast to AM251, there is a distinct lack of activation of the brain reward centres, such as the ventral tegmental area, nucleus accumbens and orbitofrontal cortex, which normally form a functional activity signature for the central action of synthetic CB₁ receptor inverse agonists. Thus, hemopressin modulates the function of key feeding-related brain nuclei of the mediobasal hypothalamus, and descending pain pathways of the PAG and DR, and not higher limbic structures. Thus, hemopressin may offer behaviourally selective effects on nociception and appetite, without engaging reward pathways.
authors.affiliation: Faculty of Life Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK. garron.dodd@manchester.ac.uk
authors.forename: Garron T
authors.initials: GT
authors.lastname: Dodd
authors.forename: Amy A
authors.initials: AA
authors.lastname: Worth
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Hodkinson
authors.forename: Raj K
authors.initials: RK
authors.lastname: Srivastava
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
authors.forename: Steve R
authors.initials: SR
authors.lastname: Williams
authors.forename: Simon M
authors.initials: SM
authors.lastname: Luckman
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002186:Cannabinoids / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D006454:Hemoglobins / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D007033:Hypothalamus, Middle / Q000187:drug effects* / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D010487:Periaqueductal Gray / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D011897:Random Allocation; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012528:Satiety Response / Q000187:drug effects
chemical_list: D001067:Appetite Depressants; C578453:CNR1 protein, mouse; D002186:Cannabinoids; D006454:Hemoglobins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C473218:hemopressin; C103505:AM 251