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