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Brain interleukin-1β and tumor necrosis factor-α are involved in lipopolysaccharide-induced delayed rectal allodynia in awake rats

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Abstract

Recently, we have developped a model of delayed (12 h) increase in sensitivity (allodynia) to rectal distension (RD) induced by intraperitoneal lipopolysaccharide (LPS) in awake rats. Thus, we examined whether central interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) are involved in LPS response. Abdominal contractions (criterion of visceral pain) were recorded in rats equipped with intramuscular electrodes. RDs were performed at various times after pharmacological treatments. RD induced abdominal contractions from a threshold volume of distension of 0.8 ml. At lowest volume (0.4 ml), this number was significantly increased 12 h after LPS. Intracerebroventricular (i.c.v.) injection of IL-1 receptor antagonist, IL-1β converting enzyme inhibitor or recombinant human TNF-α soluble receptor reduced LPS-induced increase of abdominal contractions at 0.4 ml volume of distension. When injected i.c.v., recombinant human IL-1β and recombinant bovine TNF-α reproduced LPS response at 9 and 12 h and at 6 and 9 h, respectively. These data suggest that IL-1β and TNF-α act centrally to induce delayed rectal hypersensitivity and that central release of these cytokines is responsible of LPS-induced delayed (12 h) rectal allodynia.

Introduction

Lipopolysaccharides (LPS) are bioactive components of gram negative bacterial cell wall, also known as endotoxins. Peripherally administered, LPS cause a variety of “illness” responses including physiological (e.g., activation of the hypothalamic-pituitary-adrenal axis) and behavioral disturbances (e.g., decrease food intake, social avoidance), similar to those observed during infection and inflammation [21]. Many of these behavioral and physiological changes are mimicked by pro-inflammatory cytokines, synthetized and released by immune cells that are stimulated by the illness-inducing pathogen or substance. Among them, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) appear to play a key role in the orchestration of these symptoms [40].

It was reported that agents that induce illness also produce somatic hyperalgesia [44]. Indeed, intraperitoneal injection of LPS has been found to induce long-lasting hyperalgesia in diverse somatic pain models [42], linked to the peripheral release of IL-1 and TNF-α from monocytes and macrophages. Given systemically or intradermally, these cytokines decrease thresholds required for thermal and mechanical stimuli to activate C-fibers, presumably by direct and/or indirect action at peripheral terminals 11, 43. Moreover, LPS-induced cutaneous hyperalgesia can be blocked by systemic administration of IL-1 or TNF-α receptor antagonists [43]. Somatic hyperalgesia observed after peripheral administration of these two pro-inflammatory cytokines can also be found after their central administrations. Indeed, intracerebroventricular (i.c.v.) injection of IL-1β and TNF-α can produce cutaneous hyperalgesia 33, 36 but also somatic analgesia, these responses depending upon the dose 4, 46 and the central site of microinjection [35]. After peripheral administration of endotoxin, pro-inflammatory cytokine messenger RNAs (mRNA) are produced in microglial cells, astrocytes, endothelia, ependymal cells and possibly neurons in the brain 15, 24, 41. This central release plays a role in LPS-induced illness since manifestations of illness are blocked by intracerebroventricular administration of IL-1β receptor antagonists [38].

Recently, we have shown that a relative high dose of LPS (1 mg/kg)—yet never lethal—produces visceral hypersensitivity characterized by a delayed (12 h) lowering threshold of rectal distension-induced pain, or allodynia, in awake rats [10]. Consequently, the present series of experiments was designed to determine the involvement of brain IL-1β and TNF-α, two selected pro-inflammatory cytokines, on LPS-induced delayed visceral hypersensitivity.

Section snippets

Animal preparation

Male Wistar rats (Harlan, Gannat, France), weighing 200–250 g, were surgically prepared for electromyography, according to a previously described technique [39]. Rats were anaesthetized by intraperitoneal (i.p.) injection of acepromazine (Calmivet, Vetoquinol, Lure, France) and ketamine (Imalgene 1000, Rhône-Mérieux, Lyon, France) at doses of 0.6 and 120 mg/kg, respectively. Three groups of three electrodes of NiCr wire (60 cm length and 80 μm diameter) were implanted bilaterally in the

LPS, central IL-1β and rectal allodynia

As previously described [30], RD increased the frequency of abdominal contractions in a distension volume-dependent manner. A volume of 0.8 ml was determined as the threshold where RD induced a significant increase of the number of abdominal contractions compared to the pre-distension level. Intraperitoneal injection of LPS (1 mg/kg) significantly increased (p < 0.05) the number of abdominal contractions for the volume of 0.4 ml, 3 h (11.0 ± 1.8, t(6) = 3.89, p = 0.008), 9 h (10.5 ± 2.5, t(7) =

Discussion

This study demonstrates that IL-1 receptor antagonist or IL-1 converting enzyme inhibitor, as well as TNF-α soluble receptor, all injected i.c.v., suppress LPS-induced delayed (12 h) rectal allodynia suggesting that brain IL-1β and TNF-α participate to LPS effect on visceral sensitivity. The role of IL-1β and TNF-α in the genesis of LPS-induced rectal allodynia is confirmed by the fact that central administration of rhIL-1β and rboTNF-α mimick the effects of LPS.

Injected i.p., LPS induce a well

Acknowledgements

We thank Lucien Ressayre and Ingrid Lorette for technical assistance, Institut National de la Recherche Agronomique and Solvay-Pharma Laboratories for their financial support.

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