Leptin replacement restores supraspinal cholinergic antinociception in leptin-deficient obese mice.
A single gene deletion causes lack of leptin and obesity in B6.V-Lep(ob) (obese; ob) mice compared with wild-type C57BL/6J (B6) mice. This study compared the phenotype of nociception and supraspinal antinociception in obese and B6 mice by testing 2 hypotheses: (1) microinjection of cholinomimetics or an adenosine receptor agonist, but not morphine, into the pontine reticular formation (PRF) is antinociceptive in B6 but not obese mice, and (2) leptin replacement in obese mice attenuates differences in nociceptive responses between obese and B6 mice. Adult male mice (n = 22) were implanted with microinjection guide tubes aimed for the PRF. The PRF was injected with neostigmine, carbachol, nicotine, N(6)-p-sulfophenyladenosine (SPA), morphine, or saline (control), and latency to paw withdrawal (PWL) from a thermal stimulus was recorded. B6 and ob mice did not differ in PWL after saline microinjection into the PRF. Neostigmine, carbachol, and SPA caused PWL to increase significantly in B6 but not obese mice. An additional 15 obese mice were implanted with osmotic pumps that delivered leptin for 7 days. Leptin replacement in obese mice restored the analgesic effect of PRF neostigmine to the level displayed by B6 mice. The results show for the first time that leptin significantly alters supraspinal cholinergic antinociception.


CONCLUSIONS
This study specifies a brain region (the pontine reticular formation), cholinergic neurotransmission, and a protein (leptin) modulating thermal nociception. The results are relevant for efforts to understand the association between obesity, disordered sleep, and hyperalgesia.
Wang
Wenfei
W
Department of Anesthesiology, University of Michigan, Ann Arbor, MI 48109-5615, USA.
Baghdoyan
Helen A
HA
Lydic
Ralph
R
D000109:Acetylcholine / Q000378:metabolism*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D006358:Hot Temperature; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009020:Morphine / Q000494:pharmacology; D009388:Neostigmine / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology; D009765:Obesity / Q000235:genetics / Q000503:physiopathology*; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology*; D010147:Pain Measurement; D011149:Pons / Q000187:drug effects / Q000503:physiopathology*; D013997:Time Factors
D018679:Cholinergic Agonists; D002800:Cholinesterase Inhibitors; D020738:Leptin; C109113:N(6)-(4-sulfophenyl)adenosine; D009388:Neostigmine; D009538:Nicotine; D009020:Morphine; D002217:Carbachol; D000241:Adenosine; D000109:Acetylcholine