Neuro-immune communication: role of the vagus nerve : an electrophysiological study

Abstract

Defence mechanisms involve close interactions between the nervous and immune systems following an immune challenge. The vagal pathways which modulate major visceral functions under normal conditions are also important neural pathways for the transmission of information on peripheral conditions to the CNS. The aim of this thesis was to investigate the effects of CCK-8 and IL-1[beta] on gastric vagal afferent (VA) and vagal efferent (VE) activity, including the involvement of specific CCK receptors, in conditions of partial or total vagotomy. To this purpose the mass nerve activity of the vagus nerve was recorded by bipolar platinum wire electrode in anaesthetised rats. Drugs were applied either intravenously (i.v.) or into the cisterna magna (i.c.m.).

The effect of 1 nmol (bolus dose) i.v. of CCK-8 on VA activity recorded before and 2 hours after the injection of 2-4 [my]g·kg-1 IL-1[beta] was augmented by 183 ± 14 to 255 t 27 %, with shortening of the main latency of the response. This demonstrates that the response of visceral afferents to CCK-8 was sensitized by IL-1[beta] which may be one of the peripheral mechanisms of cytokine-induced anorexia.

The effect of CCK-8 on VE activity was more pronounced in conditions of partial than with total vagotomy (decrease to 28 ± 6 % vs 56 ± 2 % 30 s after I nmol) and could be blocked by the CCKA antagonist, L- 364,718 (10-100 x 10-6 g i.v. or I X 10-6 g i.C.M.) but not by CCKB antagonist, L-365,260. This shows that only the CCKA receptors are involved in the reflex inhibition of gastric VE activity in conditions of partial and total vagotomy.

OLETF rats, an animal model for NIDDM (non-insulin-dependent diabetes mellitus) and obesity, congenitally lack CCKA receptor gene expression. VA of OLETF rats were sensitive to CCK-8 (3 nmol·kg-1 i.v.) and the response was not abolished by L-365,260. Contribution of novel (non-CCKA, non-CCKB) receptors in the response of the VA to CCK-8 in OLETF rats was implicated. The effect of IL-1[beta] (2 [my]g·kb-1 on the VA activity in OLETF rats was more pronounced than in the control strain, possibly demonstrating one of the mechanisms of augmented illness responsiveness in obese individuals.

The effect of IL-1[beta] on VE activity was dependent on the integrity of vagal afferents. A dose which did not activate VA (1 [my]g·kg-1 induced a decrease in VE activity in partly vagotomized animals. This effect was diminished by pre-administration of indomethacin (5 mg.kg-1) or by total subdiaphragmatic vagotomy.

In summary, our results show that both subdiaphragmatic vagal afferents and efferents are involved in responses to exogenous IL-1[beta] and CCK-8. Altered sensitivity of vagal pathways may be important in the development of illness responses in both normal and obese individuals.