Research reportIntrathecal interleukin-1β administration induces thermal hyperalgesia by activating inducible nitric oxide synthase expression in the rat spinal cord
Introduction
Interleukin-1β (IL-1β), a pro-inflammatory cytokine, is involved in the immune response and signal transduction both in the periphery and the central nervous system (CNS) [13], [14], [17], [18], [28], [36]. It is released during inflammatory and neuropathic pain conditions [8], [34], [39], [43]. Samad et al. [34] found that injection of complete Freund's adjuvant (CFA) into the rat's hindpaw induced peripheral inflammation and IL-1β upregulation (>10,000-fold) in the inflamed hindpaw soon after CFA administration; this effect lasted for several days and was correlated with the peripheral inflammation. Moreover, in their study, the IL-1β concentration in the CSF was increased 50- and 20-fold, at 2 and 4 h, respectively, after CFA injection, and this was followed by an increased cyclooxygenase-2 (COX-2) level in the spinal cord. They also found that intrathecal (i.t.) injection of IL-1β (50 ng) induced a 30-fold increase in COX-2 mRNA levels in the rat spinal cord. Administration of IL-1β produces hyperalgesia; in contrast, blockade of IL-1β reduces pain [10], [30], [32], [34], [35], [37]. It is apparent that IL-1β is an important mediator in the cross-talk between the nervous and immune systems, and also participates in modulation of the nociceptive threshold.
Nitric oxide (NO), a short-lived diffusible molecule of great biological importance, plays a key role in host defense, signal transduction, and neurotransmission. There is increasing evidence that NO is also involved in nociceptive processing after inflammation and neuropathy [26]. Three isoforms of nitric oxide synthase (NOS) are known; two are constitutively expressed (nNOS and eNOS), and the third is inducible NOS (iNOS). Both nNOS (neuronal) and eNOS (endothelial) are activated in response to physical stimuli, and rapidly produce low levels of NO. In contrast, iNOS is activated by stimuli such as IL-1β, and produces a high level of NO over a long period of time [6], [23]. Upregulation of NOS expression and subsequent NO production in the spinal cord contributes to pain following nociceptive stimulation in animals [20], [26], [33], [41], [46]. i.t. administration of NOS inhibitors significantly reduces nociceptive behavior in response to peripheral inflammation [31], [33], [46]. Moreover, IL-1β was found to increase both iNOS expression and NO production in cultured cells [12], [15]. Although both IL-1β and the NOS-NO cascade have been suggested to modulate nociception, there is little information concerning the interaction between IL-1β and the iNOS-NO cascade in the spinal cord. We hypothesized that, i.t. IL-1β causes a markedly increased NO production via induction of iNOS expression in the rat spinal cord. If an IL-1β induced elevation in NO can be confirmed, it might reveal a significant pathophysiological pathway of intrathecal IL-1β-induced thermal hyperalgesia. The present study was designed to examine the role of the NOS-NO cascade, and its correspondence to nociceptive behaviors, in the spinal cord of i.t. IL-1β-treated rats.
Section snippets
Construction and implantation of the intrathecal catheter and microdialysis probe
The i.t. catheter was constructed using a 9-cm long polyethylene (PE5) tube and a 3.5-cm long silastic tube. The silastic tube was inserted into the PE5 tube and sealed with epoxy resin and silicon rubber. In addition, the spinal microdialysis probe construction technique was modified and adapted in previous studies [21], [45]. The microdialysis probe was constructed using two 7 cm PE5 tubes (0.008 inch inner diameter, 0.014 inch outer diameter) and a 4-cm cuprophan hollow fiber (300 μm outer
Effect of iNOS inhibitor 1400W on IL-1β-induced thermal hyperalgesia
After i.t. injection of IL-1β (100 ng), thermal hyperalgesia was observed with the PWL reduced to 50–60% of baseline level between 4 and 24 h (Fig. 1). This hypersensitivity to the heat was significantly increased at 4 h, peaked at 6 h, and lasted for 24 h after IL-1β i.t. administration. Either aCSF or 1400W (10 μg) alone did not affect the PWL to the heat, whereas i.t. pretreatment with 1400W (10 μg) 1 h prior to IL-1β (100 ng) injection significantly attenuated the IL-1β-induced thermal
Discussion
In the present study, thermal hyperalgesia was observed 4 h after IL-1β injection and lasted for 24 h. The iNOS selective inhibitor 1400W prevented this thermal hyperalgesia and the corresponding biochemical changes. I.t. administration of IL-1β induced iNOS protein expression and the subsequent NO release, in a time-dependent manner, in the rat spinal cord. iNOS protein induction and activation were observed at 4 h after IL-1β injection, peaked at 6 h, then declined gradually, and disappeared
Acknowledgements
The authors wish to thank Dr. Yoshito Takano for his helpful communications on the algesic effect of spinal IL-1β and Mr. Yao-Chang Chen for the statistical analysis. This work was supported by grants from the National Science Council (NSC 91-2314-B-075-070) and Ministry of Defense (DOD-93-2-08) of the Republic of China.
References (47)
- et al.
Induction of nitric oxide synthase and over-production of nitric oxide by interleukin-1β in cultured lacrimal gland acinar cells
Exp. Eye Res
(2003) - et al.
Nitric oxide synthase from cerebellum catalyzes the formation of equimolar quantities of nitric oxide and citrulline from l-arginine
Biochem. Biophys. Res. Commun
(1992) - et al.
Interleukin-1β activates forebrain glial cells and increases nitric oxide production and cortical glutamate and GABA release in vivo: implications for Alzheimer's disease
Neuroscience
(1999) - et al.
Brain interleukin-1β and tumor necrosis factor-alpha are involved in lipopolysaccharide-induced delayed rectal allodynia in awake rats
Brain Res. Bull
(2000) Nitric oxide in immunity and inflammation
Int. Immunopharmacol
(2001)- et al.
Cytokine and growth factor immunohistochemical spinal profiles in two animal models of mononeuropathy
Brain Res
(1997) - et al.
Pancreatic beta-cell damage mediated by beta-cell production of interleukin-1. A novel mechanism for virus-induced diabetes
J. Biol. Chem
(2001) - et al.
Interleukin 1-induced cyclooxygenase and nitric oxide synthase gene expression in the rat dorsal root ganglia is modulated by antioxidants
Neuroscience
(2001) - et al.
Increase of nociceptive threshold induced by intrathecal injection of interleukin-1β in normal and carrageenan inflammatory rat
Cytokine
(2002) - et al.
Increased plasma levels of interleukin-1, interleukin-6 and α-1-antichymotrypsin in patients with Alzheimer's disease: peripheral inflammation or signals from the brain?
J. Neuroimmunol
(2000)
Regulation and immunohistochemical localization of nitric oxide synthases and soluble guanylyl cyclase in mouse spinal cord following nociceptive stimulation
Neurosci. Lett
The spinal loop dialysis catheter: characterization of use in the unanesthetized rat
J. Neurosci. Methods
The possible role of glia in nociceptive processing and hyperalgesia in the spinal cord of the rat
Neuropharmacology
Regulation of biosynthesis of nitric oxide
J. Biol. Chem
Intracerebroventricular injection of interleukin-1β induces hyperalgesia in rats
Brain Res
Intracerebroventricular injection of interleukin-1β enhances nociceptive neuronal responses of the trigeminal nucleus caudalis in rats
Brain Res
Peripheral nitric oxide in carrageenan-induced inflammation
Brain Res
Induction of pro-inflammatory cytokine mRNAs in the brain after peripheral injection of subseptic doses of lipopolysaccharide in the rat
J. Neuroimmunol
Intrathecally administered endotoxin or cytokines produce allodynia, hyperalgesia and changes in spinal cord neuronal responses to nociceptive stimuli in the rat
Eur. J. Pain
A nitric oxide synthesis inhibitor (l-NAME) reduces licking behavior and Fos-labeling in the spinal cord of rats during formalin-induced inflammation
Pain
Effect of spinal nitric oxide inhibition on capsaicin-induced nociceptive response
Life Sci
Combined epineurial therapy with neutralizing antibodies to tumor necrosis factor-alpha and interleukin-1 receptor has an additive effect in reducing neuropathic pain in mice
Neurosci. Lett
Neutralizing antibodies to interleukin 1-receptor reduce pain associated behavior in mice with experimental neuropathy
Neurosci. Lett
Cited by (130)
Astrocytic and microglial interleukin-1β mediates complement C1q-triggered orofacial mechanical allodynia
2023, Neuroscience ResearchCCR4 antagonist (C021) influences the level of nociceptive factors and enhances the analgesic potency of morphine in a rat model of neuropathic pain
2020, European Journal of Pharmacology