Evidence that exogenous and endogenous fractalkine can induce spinal nociceptive facilitation in rats.
Recent evidence suggests that spinal cord glia can contribute to enhanced nociceptive responses. However, the signals that cause glial activation are unknown. Fractalkine (CX3C ligand-1; CX3CL1) is a unique chemokine expressed on the extracellular surface of spinal neurons and spinal sensory afferents. In the dorsal spinal cord, fractalkine receptors are primarily expressed by microglia. As fractalkine can be released from neurons upon strong activation, it has previously been suggested to be a neuron-to-glial signal that induces glial activation. The present series of experiments provide an initial investigation of the spinal pain modulatory effects of fractalkine. Intrathecal fractalkine produced dose-dependent mechanical allodynia and thermal hyperalgesia. In addition, a single injection of fractalkine receptor antagonist (neutralizing antibody against rat CX3C receptor-1; CX3CR1) delayed the development of mechanical allodynia and/or thermal hyperalgesia in two neuropathic pain models: chronic constriction injury (CCI) and sciatic inflammatory neuropathy. Intriguingly, anti-CX3CR1 reduced nociceptive responses when administered 5-7 days after CCI, suggesting that prolonged release of fractalkine may contribute to the maintenance of neuropathic pain. Taken together, these initial investigations of spinal fractalkine effects suggest that exogenous and endogenous fractalkine are involved in spinal sensitization, including that induced by peripheral neuropathy.
Milligan
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ED
Department of Psychology & the Center for Neuroscience, University of Colorado at Boulder, Boulder, CO 80309-0345, USA.
Zapata
V
V
Chacur
M
M
Schoeniger
D
D
Biedenkapp
J
J
O'Connor
K A
KA
Verge
G M
GM
Chapman
G
G
Green
P
P
Foster
A C
AC
Naeve
G S
GS
Maier
S F
SF
Watkins
L R
LR
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000073883:CX3C Chemokine Receptor 1; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C / Q000008:administration & dosage / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D007278:Injections, Spinal; D008026:Ligation; D008297:Male; D008565:Membrane Proteins / Q000008:administration & dosage / Q000187:drug effects / Q000378:metabolism*; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors / Q000378:metabolism; D015728:Receptors, HIV / Q000037:antagonists & inhibitors / Q000378:metabolism; D020426:Sciatic Neuropathy / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology
D000906:Antibodies; D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; C515540:Cx3cl1 protein, rat; D008565:Membrane Proteins; D018121:Receptors, Cytokine; D015728:Receptors, HIV