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An initial investigation of spinal mechanisms underlying pain enhancement induced by fractalkine, a neuronally released chemokine.
Eur J Neurosci. 2005 Dec; 22(11):2775-82.EJ

Abstract

Fractalkine is a chemokine that is tethered to the extracellular surface of neurons. Fractalkine can be released, forming a diffusible signal. Spinal fractalkine (CX3CL1) is expressed by sensory afferents and intrinsic neurons, whereas its receptor (CX3CR1) is predominantly expressed by microglia. Pain enhancement occurs in response both to intrathecally administered fractalkine and to spinal fractalkine endogenously released by peripheral neuropathy. The present experiments examine whether fractalkine-induced pain enhancement is altered by a microglial inhibitor (minocycline) and/or by antagonists/inhibitors of three putative glial products implicated in pain enhancement: interleukin-1 (IL1), interleukin-6 (IL6) and nitric oxide (NO). In addition, it extends a prior study that demonstrated that intrathecal fractalkine-induced mechanical allodynia is blocked by a neutralizing antibody to the rat fractalkine receptor, CX3CR1. Here, intrathecal anti-CX3CR1 also blocked fractalkine-induced thermal hyperalgesia. Furthermore, blockade of microglial activation with minocycline prevented both fractalkine-induced mechanical allodynia (von Frey test) and thermal hyperalgesia (Hargreaves test). Microglial activation appears to lead to the release of IL1, given that pretreatment with IL1 receptor antagonist blocked both fractalkine-induced mechanical allodynia and thermal hyperalgesia. IL1 is not the only proinflammatory cytokine implicated, as a neutralizing antibody to rat IL6 also blocked fractalkine-induced pain facilitation. Lastly, NO appears to be importantly involved, as l-NAME, a broad-spectrum NO synthase inhibitor, also blocked fractalkine-induced effects. Taken together, these data support that neuronally released fractalkine enhances pain via activation of spinal cord glia. Thus, fractalkine may be a neuron-to-glia signal triggering pain facilitation.

Authors+Show Affiliations

Department of Psychology & Center for Neuroscience, University of Colorado at Boulder, Boulder, CO 80309-0345, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16324111

Citation

Milligan, E, et al. "An Initial Investigation of Spinal Mechanisms Underlying Pain Enhancement Induced By Fractalkine, a Neuronally Released Chemokine." The European Journal of Neuroscience, vol. 22, no. 11, 2005, pp. 2775-82.
Milligan E, Zapata V, Schoeniger D, et al. An initial investigation of spinal mechanisms underlying pain enhancement induced by fractalkine, a neuronally released chemokine. Eur J Neurosci. 2005;22(11):2775-82.
Milligan, E., Zapata, V., Schoeniger, D., Chacur, M., Green, P., Poole, S., Martin, D., Maier, S. F., & Watkins, L. R. (2005). An initial investigation of spinal mechanisms underlying pain enhancement induced by fractalkine, a neuronally released chemokine. The European Journal of Neuroscience, 22(11), 2775-82.
Milligan E, et al. An Initial Investigation of Spinal Mechanisms Underlying Pain Enhancement Induced By Fractalkine, a Neuronally Released Chemokine. Eur J Neurosci. 2005;22(11):2775-82. PubMed PMID: 16324111.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - An initial investigation of spinal mechanisms underlying pain enhancement induced by fractalkine, a neuronally released chemokine. AU - Milligan,E, AU - Zapata,V, AU - Schoeniger,D, AU - Chacur,M, AU - Green,P, AU - Poole,S, AU - Martin,D, AU - Maier,S F, AU - Watkins,L R, PY - 2005/12/6/pubmed PY - 2006/2/8/medline PY - 2005/12/6/entrez SP - 2775 EP - 82 JF - The European journal of neuroscience JO - Eur. J. Neurosci. VL - 22 IS - 11 N2 - Fractalkine is a chemokine that is tethered to the extracellular surface of neurons. Fractalkine can be released, forming a diffusible signal. Spinal fractalkine (CX3CL1) is expressed by sensory afferents and intrinsic neurons, whereas its receptor (CX3CR1) is predominantly expressed by microglia. Pain enhancement occurs in response both to intrathecally administered fractalkine and to spinal fractalkine endogenously released by peripheral neuropathy. The present experiments examine whether fractalkine-induced pain enhancement is altered by a microglial inhibitor (minocycline) and/or by antagonists/inhibitors of three putative glial products implicated in pain enhancement: interleukin-1 (IL1), interleukin-6 (IL6) and nitric oxide (NO). In addition, it extends a prior study that demonstrated that intrathecal fractalkine-induced mechanical allodynia is blocked by a neutralizing antibody to the rat fractalkine receptor, CX3CR1. Here, intrathecal anti-CX3CR1 also blocked fractalkine-induced thermal hyperalgesia. Furthermore, blockade of microglial activation with minocycline prevented both fractalkine-induced mechanical allodynia (von Frey test) and thermal hyperalgesia (Hargreaves test). Microglial activation appears to lead to the release of IL1, given that pretreatment with IL1 receptor antagonist blocked both fractalkine-induced mechanical allodynia and thermal hyperalgesia. IL1 is not the only proinflammatory cytokine implicated, as a neutralizing antibody to rat IL6 also blocked fractalkine-induced pain facilitation. Lastly, NO appears to be importantly involved, as l-NAME, a broad-spectrum NO synthase inhibitor, also blocked fractalkine-induced effects. Taken together, these data support that neuronally released fractalkine enhances pain via activation of spinal cord glia. Thus, fractalkine may be a neuron-to-glia signal triggering pain facilitation. SN - 0953-816X UR - https://www.unboundmedicine.com/medline/citation/16324111/An_initial_investigation_of_spinal_mechanisms_underlying_pain_enhancement_induced_by_fractalkine_a_neuronally_released_chemokine_ L2 - https://doi.org/10.1111/j.1460-9568.2005.04470.x DB - PRIME DP - Unbound Medicine ER -