Elsevier

Neuropharmacology

Volume 45, Issue 5, October 2003, Pages 605-611
Neuropharmacology

Vagal modulation of spinal nicotine-induced inhibition of the inflammatory response mediated by descending antinociceptive controls

https://doi.org/10.1016/S0028-3908(03)00224-7Get rights and content

Abstract

Noxious stimuli activate neuroendocrine axes, inhibiting inflammation, an effect that is powerfully attenuated by ongoing activity in subdiaphragmatic vagal afferents. To evaluate whether this inhibitory effect of vagal afferent activity is mediated by descending antinociceptive control, we tested whether antagonizing descending antinociceptive controls: (i) enhances the inhibition of inflammation produced by spinal nicotine (which stimulates central terminals of nociceptors) and (ii) occludes the enhancing effect of subdiaphragmatic vagotomy, in the rat. Spinal intrathecal co-administration of the α-adrenergic receptor antagonist phentolamine and the non-selective opioid receptor antagonist naloxone, and acute subdiaphragmatic vagotomy each produced enhancement, with similar magnitude, of nicotine-induced inhibition of plasma extravasation, produced by the potent inflammatory mediator, bradykinin. The combination of subdiaphragmatic vagotomy and intrathecal receptor antagonists, however, produced no further enhancement compared to each treatment alone. These findings support the suggestion that activity in descending antinociceptive controls modulates noxious stimulus-induced inhibition of inflammation and the vagal modulation of noxious stimulus-induced inhibition of inflammation is mediated by descending antinociceptive controls.

Introduction

Pain, such as that associated with inflammation, can produce inhibition of an inflammatory response, an effect mediated by neuroendocrine mechanisms (Green et al., 1997, Miao et al., 2000, Miao and Levine, 1999). This feedback inhibition of inflammation is under potent control by afferent activity in the subdiaphragmatic vagus nerve (Miao et al., 1997b). Thus, subdiaphragmatic vagotomy, or celiac plus celiac accessory branch vagotomy, produces a marked left shift in the dose-response curve for noxious stimulus-induced inhibition of plasma extravasation produced by bradykinin (Miao et al., 1997b), a potent inflammatory mediator (Bock and Longmore, 2000, Calixto et al., 2000). Vagotomy also enhances the potency of spinal intrathecal nicotine, which also inhibits bradykinin-induced plasma extravasation—possibly by acting on the central terminals of primary afferent nociceptors (Genzen et al., 2001, Miao et al., 2001, Steen and Reeh, 1993)—by six orders of magnitude (Miao et al., 1994). In this study we evaluate the hypotheses that: 1) descending antinociceptive controls inhibit intrathecal nicotine-induced attenuation of bradykinin-induced plasma extravasation, and 2) subdiaphragmatic vagotomy enhances noxious stimulus-induced inhibition of inflammation by decreasing activity in descending antinociceptive controls.

Section snippets

Methods

The experiments were performed on male Sprague-Dawley rats (300–400 g). Rats were anesthetized by intraperitoneal injection of sodium pentobarbital (65 mg/kg, Abbott Lab., Chicago, IL) for both surgical procedures and knee joint perfusion experiments. Animal care and use conformed to the NIH guidelines for the care and use of experimental animals. The University of California at San Francisco, Committee on Animal Research, approved all experimental protocols used in these experiments.

Intrathecal co-administration of α-adrenergic and opioid receptor antagonists potentiate the anti-inflammatory effect of intrathecal nicotine

To inhibit descending antinociceptive controls we intrathecally co-administered phentolamine (100 nmole in 10 μl) and naloxone (100 nmole in 10 μl), receptor antagonists for α-adrenergic and opioid receptors, respectively, known to be involved in descending antinociceptive controls. This produced a marked left shift in the dose response relationship for intrathecal nicotine-induced inhibition of bradykinin-induced plasma extravasation in the knee joint of the rat (Fig. 1(A); Statistics; Table 1

Discussion

We have previously demonstrated that activity in subdiaphragmatic vagal afferents potently attenuates noxious stimulus- and intrathecal nicotine-induced inhibition of inflammation (Miao et al., 1997b). However, the central nervous system circuitry by which vagal afferent activity modulates noxious stimulus-induced inhibition of the inflammatory response is still poorly understood. To evaluate underlying central nervous system circuitry, we have evaluated two hypotheses, that descending

Acknowledgements

This work was supported by a grant from the National Institutes of Health (AR32634).

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