Introduction ment, differentiation [31,35], survival [19], regeneration
Brain Research 879 2000 216–225 www.elsevier.com locate bres
Interactive report
Intrathecal anti-IL-6 antibody and IgG attenuates peripheral nerve injury-induced mechanical allodynia in the rat: possible immune
1
modulation in neuropathic pain
a , b
a a,b
Janice L. Arruda , Sarah Sweitzer , Maria D. Rutkowski , Joyce A. DeLeo
a
Department of Anesthesiology , Dartmouth-Hitchcock Medical Center, HB 7125, 1 Medical Center Drive, Lebanon, NH 03756, USA
b
Department of Pharmacology , Dartmouth-Hitchcock Medical Center, HB 7125, 1 Medical Center Drive, Lebanon, NH 03756, USA
Accepted 13 August 2000
Abstract
Interleukin-6 IL-6 is a pleiotrophic cytokine with a diverse range of actions including the modulation of the peripheral and central nervous system. We have previously shown significant IL-6 protein and messenger RNA elevation in rat spinal cord following peripheral
nerve injury that results in pain behaviors suggestive of neuropathic pain. These spinal IL-6 levels correlated directly with the mechanical allodynia intensity following nerve injury. In the current study, we sought to determine whether it is possible to attenuate mechanical
allodynia and or alter spinal glial activation resulting from peripheral nerve injury by specific manipulation of IL-6 with neutralizing antibodies or by global immune modulation utilizing immunogamma-globulin IgG. Effects of peripheral administration of normal goat
IgG and intrathecal i.t. administration of IL-6 neutralizing antibody, normal goat or normal rat IgG on mechanical allodynia associated with L5 spinal nerve transection were compared. Spinal glial activation was assessed at day 10 post surgery by immunohistochemistry.
Low dose 0.01–0.001 mg goat anti-rat IL-6 i.t. administration P50.025 significantly decreased allodynia and trended towards significance at the higher dose 0.08 mg to 0.008 mg, P50.062. Low doses 0.01–0.001 mg i.t. normal goat and rat IgG significantly
attenuated mechanical allodynia, but not at higher doses 0.08–0.008 mg; P50.001 for both goat and rat IgG. Peripherally administered normal goat IgG 30 or 100 mg kg did not attenuate mechanical allodynia. Spinal glial activation was unaltered by any treatment. These
data provide further evidence for the role of central IL-6 and neuroimmune modulation in the etiology of mechanical allodynia following peripheral nerve injury.
2000 Elsevier Science B.V. All rights reserved.
Theme : Sensory systems
Topic : Pain modulation: pharmacology
Keywords : Astrocytes; Glial fibrillary acidic protein; Interleukin-6; IVIg therapy; Microglia; Neuropathic pain
1. Introduction ment, differentiation [31,35], survival [19], regeneration
and degeneration in both the peripheral and central nervous Interleukin 6 IL-6 is a pleitrophic cytokine that is
systems CNS. involved in a diverse range of functions within the body
IL-6 has been implicated as a significant factor in the including the modulation of proliferation, differentiation
central nervous system’s response to injury [2,21,23]. This and maturation of progenitor cells [28], control of cellular
proinflammatory cytokine plays a key role in peripheral metabolic activities [17], the immune system cascade, and
nerve injury-induced mechanical allodynia and thermal modulation within the nervous system. There is increasing
hyperalgesia in both rodents and humans [13,18,37]. We evidence that supports a role of IL-6 in neuronal develop-
have previously demonstrated a direct relationship between the increase in both mechanical allodynia increased
sensitivity to a non-noxious stimulus and IL-6 immuno-
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Published on the World Wide Web on 28 August 2000.
reactive-like protein in the spinal cord in a sciatic
Corresponding author. Tel.: 11-603-650-6205; fax: 11-603-650-
cryoneurolysis model of mononeuropathy [13]. In addition,
4928. E-mail address
: janice.l.pahldartmouth.edu J.L. Arruda.
intrathecally administered human recombinant IL-6 in the
0006-8993 00 – see front matter
2000 Elsevier Science B.V. All rights reserved. P I I : S 0 0 0 6 - 8 9 9 3 0 0 0 2 8 0 7 - 9
J .L. Arruda et al. Brain Research 879 2000 216 –225
217
absence of nerve injury was able to produce touch evoked these therapies, neutralizing goat anti-IL-6 was adminis-
allodynia in rats and produced thermal hyperalgesia in the tered intrathecally i.t. and normal rat or goat IgG
sciatic cryoneurolysis model [13]. Furthermore, our labora- antibodies were given either i.t. or via intravenous i.v.
tory has shown that neurons of the spinal cord produce injection. To assess alterations in this mononeuropathy
IL-6 messenger RNA in response to peripheral nerve model due to the various treatments, tactile sensitivity
injury resulting in neuropathic pain behaviors [3]. Recently using von Frey filaments and spinal glial activation were
it has been demonstrated that in the chronic constriction assessed. Glial activation, in particular astrocytic, may
injury model, cutaneous heat and pressure hypersensitivity have a principle role in nociceptive processing and in the
was not elicited in mice with a null mutation of the IL-6 thermal and mechanical hyperalgesia and or allodynia
gene as compared to the wild type controls [33]. produced by peripheral nerve injury [32]. Efficacy of the
Along with these direct relationships between IL-6 and pharmacological interventions was determined by their
the CNS response to injury, recent literature also impli- ability to significantly attenuate one nerve-injured induced
cates possible indirect effects of IL-6 through its’ ability to behavioral modality, mechanical allodynia. Our results
modulate classic pain mediators in the CNS milieu. For reveal a potentially novel mechanism of modulating spinal
example, in a series of related in vivo and in vitro studies, neuroinflammation that may ultimately translate into new,
it was shown that the concentration of nitrate increased in non-addictive xenobiotics for the treatment of chronic pain
rat hippocampus in response to IL-6 treatment, suggesting syndrome in humans.
an overproduction of nitric oxide due to the presence of IL-6 [29,30]. Recent work in our laboratory has also
revealed that in the spinal cord of L5 nerve transected