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.2009 Aug;10(8):836-43.
doi: 10.1016/j.jpain.2009.02.003. Epub 2009 Apr 19.

Leptin replacement restores supraspinal cholinergic antinociception in leptin-deficient obese mice

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Leptin replacement restores supraspinal cholinergic antinociception in leptin-deficient obese mice

Wenfei Wang et al. J Pain.2009 Aug.

Abstract

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.

Perspective: 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.

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Figures

Figure 1
Figure 1
All microinjection sites were localized to pontine reticular formation regions comprised of the oral (PnO) and caudal (PnC) pontine reticular nucleus. Microinjection sites for B6 mice (black dots, n=13), obese mice (green dots, n=8), and obese mice that received leptin (purple dots, n=15) are shown on five coronal drawings of the mouse brainstem. Numbers at the lower right of each drawing indicate distance (mm) posterior to bregma. The top left figure shows a typical cresyl violet stained tissue section with an arrow pointing to the microinjection site. The top right figure represents a sagittal view of the mouse brain with vertical lines indicating the anterior to posterior range of the microinjection sites. Brain drawings were modified from the Paxinos and Franklin mouse brain atlas.
Figure 2
Figure 2
Percent maximum potential effect (%MPE) values following microinjections into the pontine reticular formation of B6 and B6.V-Lepob (obese) mice. Graphs showing data from B6 and obese mice for each drug are presented side by side to facilitate comparison. The %MPE is a measurement of change from baseline (no injection) values. Higher %MPE values indicate a longer delay in moving the paw away from the stimulus, consistent with decreased nociception. Saline microinjections (vehicle control) produced %MPE values around 0, indicating little change from baseline (no injection) values. Asterisks indicate a significant difference from saline at designated time points.
Figure 3
Figure 3
Leptin replacement restored the antinociceptive effect of pontine reticular formation neostigmine in obese mice. Graph shows %MPE values averaged over the course of 2 h following microinjection of saline or neostigmine for obese mice, B6 mice, and obese mice that received leptin replacement. Asterisks indicate a significant difference (P<0.05) between response to neostigmine and saline.
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