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Original Article

Increased circulating rather than spinal

cytokines accompany chronic pain behaviors in

experimental bone cancer and arthritis

Line Pourtau , Amarins Nieske Heeringa , Carole Rovère , Agnès Aubert , Jean‑Louis Nahon ,
1,2
1,2
1,2
3,4
3,4
Sylvain Miraux , Jan Pieter Konsman 1,2
5,6
1 CNRS, PsychoNeuroImmunologie, Nutrition et Génétique, UMR 5226, 33076 Bordeaux, France
2 Univ. Bordeaux, PsyNuGen, UMR 5226, 33076 Bordeaux, France
3 CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, 06560 Valbonne, France
4 Univ. Nice Sophia Antipolis, 06130 Nice, France
5 CNRS, Résonance Magnétique des Systèmes Biologiques, UMR 5536, 33076 Bordeaux, France
6 Univ. Bordeaux, RMSB, UMR 5536, 33076 Bordeaux, France
ABSTRA CT

Aim: Peripheral cytokines contribute to arthritis and bone cancer pain through sensory nerve actions. However, increased spinal
cytokine and glial filament expression, coined neuroinflammation, has also been proposed to play a part in chronic pain. Therefore,
spinal cord, dorsal root ganglia and circulating cytokines were compared in murine arthritis and bone cancer models in relationship
to behavioral signs of pain. Methods: Exploratory behaviors were studied after intra‑articular complete Freund’s adjuvant or bone
intramedullary sarcoma cell injection. Nervous tissue and blood cytokine expression were determined by real‑time polymerase
chain reaction (PCR) and multiplex immunoassays, respectively. Results: PCR analysis did not reveal any hallmark of spinal
neuroinflammation in spontaneously‑behaving mice with cartilage or bone lesions. However, imposed paw stimulation during joint
inflammation increased spinal interleukin‑1β (IL‑1β) expression. Spontaneous paw guarding during rearing was displayed by animals
with joint inflammation and bone destruction and was accompanied by increased circulating IL‑6 and monocyte chemoattractant
protein‑1, respectively. In addition, dorsal root ganglia were found to constitutively express receptors for this chemotactic cytokine.
Conclusion: Our findings indicate that spinal neuroinflammation is not a necessary condition for chronic pain and suggest that
circulating cytokine action in dorsal root ganglia may contribute to experimental joint inflammation and bone cancer pain.
Key words: Arthritis, bone cancer, CCL2, cytokines, dorsal root ganglia, pain, spinal cord

INTRODUCTION
glial filament expression, coined neuroinflammation,
Painful joint inflammation affects millions of people may also contribute to pain. Indeed, both peripheral
[7]
with osteoarthritis and rheumatoid arthritis, whereas or intrathecal administration of the pro‑inflammatory
bone pain occurs in hundreds of thousands of patients cytokines interleukin‑1beta (IL‑1β) and tumor necrosis
with metastasized cancer. [1‑3] Arthritic and bone cancer factor‑alpha (TNF‑α) or of the chemotactic cytokine
pain are worsened by movement and thus reduce monocyte chemoattractant protein‑1 (MCP‑1/CCL2)
autonomy, [2,4‑6] for instance by interfering with the increase experimental pain sensitivity. [8‑14] Moreover,
capacity to prepare daily meals. peripheral and intrathecal cytokine antagonists
attenuate hyperalgesia in inflammatory and bone cancer
Local cytokine production is important in arthritis pain models. [8,15‑21] However, intrathecally‑administered
and bone cancer, but increased spinal cytokine and molecules readily spread to dorsal root ganglia
(DRG), [22] where receptor proteins for some cytokines
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are expressed, [23,24] indicating that intrathecal cytokines
Quick Response Code: or their antagonists may act centrally or peripherally.
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www.nnjournal.net
Although some studies have reported increased spinal
DOI: cytokine expression in experimental inflammatory and
10.4103/2347-8659.143680 bone cancer pain, [19,25‑28] most studies have addressed
spinal glial responses and found these to be variable. [27‑32]

Corresponding Author: Dr. Jan Pieter Konsman, CNRS UMR 5536, Résonance Magnétique des Systèmes Biologiques,
Université de Bordeaux, 146, rue Léo Saignat, 33076 Bordeaux Cedex, France. E‑mail: jan‑pieter.konsman@u‑bordeaux2.fr

Neuroimmunol Neuroinflammation | Volume 1 | Issue 3 | December 2014 153