The NK1 receptor is essential for the full expression of noxious inhibitory controls in the mouse - PubMed (original) (raw)

The NK1 receptor is essential for the full expression of noxious inhibitory controls in the mouse

H Bester et al. J Neurosci. 2001.

Abstract

Behavioral analysis of the NK1 receptor gene knock-out (NK1-/-) mouse indicated that substance P was closely involved in orchestrating the physiological and behavioral response of the animal to major environmental stressors. In particular, endogenous pain control mechanisms, such as stress-induced analgesia were substantially impaired in mutant mice, suggesting a reduction in descending inhibitory controls to the spinal cord from the brainstem. To directly test the integrity of descending controls in NK1-/- mice, we have analyzed c-Fos expression in laminae I-II of the lumbar and cervical cord and in the rostral ventromedial medulla in an experimental paradigm known to require recruitment of descending inhibitory controls. Anesthetized mice were stimulated with water at 50 degrees C either on their forepaw, hindpaw, or on both the hindpaw plus forepaw concurrently. Wild-type mice, naive or treated with an NK1 antagonist (RP67580) or its inactive isomer (RP68651), were compared with NK1-/- mice. C-Fos expression at the lumbar laminae I-II level was significantly reduced, whereas it was significantly greater in the raphe magnus and pallidus nuclei in the double stimulation situation in wild-type compared with NK1-/- mice. Blocking the NK1 receptor pharmacologically reproduced, in an enantiomere-selective manner, the data from NK1-/- mice, with no evidence for recruitment of descending inhibition at the lumbar cord level after forepaw stimulation. The present study demonstrates that the NK1 receptor is essential for the full development of noxiously evoked descending inhibition.

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Figures

Fig. 1.

Fig. 1.

Representative examples of camera lucida drawings of Fos-IR neurons (black dots) in the lumbar dorsal horn ipsilateral to the stimulus in the hindpaw-stimulated animals (HP column) and in the forepaw plus hindpaw-stimulated animals (FP + HP column). A, Wild-type animals. _B,_NK1−/− mice. C, Wild-type animals injected with the RP67580 NK1 antagonist. D, Wild-type mice injected with the NK1 antagonist isomer RP68651. Vr, Reticular part of the lamina V. Laminae I-II, Laminae I and II of the dorsal horn. Scale bar, 500 μm.

Fig. 2.

Fig. 2.

Photomicrographs of the lumbar dorsal horn (segments L4/5) ipsilateral to the stimulation. Note the reduction in the number of Fos-IR reactive neurons in wild-type animals (A, B) between a hindpaw stimulation only (A) and a forepaw plus hindpaw stimulation (B), and the absence of such an effect in NK1−/− (C, D). Scale bar, 400 μm.

Fig. 3.

Fig. 3.

Histograms of the average number per section of Fos-IR neurons evoked in the lumbar laminae I-II, in the HP (A), FP (B), and FP + HP (C) situations. ★p < 0.05; ★★p < 0.01; ★★★p < 0.001.

Fig. 4.

Fig. 4.

Histograms of the average number per section of Fos-IR neurons evoked in the lumbar laminae I-II, comparing the HP and the FP + HP situations. ★p < 0.05; ★★★p < 0.001.

Fig. 5.

Fig. 5.

Relationship between lumbar and cervical c-Fos expression in the FP + HP situation. Regression plots and correlation lines and functions of the lumbar against cervical numbers of Fos-IR neurons in laminae I-II.

Fig. 6.

Fig. 6.

Histograms of the average number per section of Fos-IR neurons evoked in the cervical laminae I-II, in the HP, FP, and FP + HP situations.

Fig. 7.

Fig. 7.

C-Fos expression in the rostral ventromedial medulla and its influence on the c-Fos expression in lumbar laminae I-II in the FP + HP situation. A, Histograms of average numbers of Fos-IR neurons observed in different raphe nuclei viewed on a schematic representation of the medulla from the Franklin and Watson (1997) atlas. ★★p < 0.01; ★★★p < 0.001. _Gi,_Gigantocellular reticular; GiA, gigantocellular reticular pars α; LPGi, lateral paragigantocellular reticular; RMg, raphe magnus; RPa, raphe pallidus. B, Correlation plots of the numbers of Fos-IR neurons in the RPa and RMg raphe nuclei. _Filled symbols_correspond to NK1−/− mice; open symbols correspond to wild-type mice.

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