TRPV1 receptor inhibition decreases CCL2-induced hyperalgesia.
Modulation of nociceptive synaptic transmission in the spinal cord is implicated in the development and maintenance of several pathological pain states. The chemokine CCL2 (C-C motif ligand 2) was shown to be an important factor in the development of neuropathic pain after peripheral nerve injury. In our experiments we have studied the effect of CCL2 application and TRPV1 (transient receptor potential vanilloid 1) receptor activation on nociceptive signaling and the modulation of synaptic transmission. Intrathecal drug application in behavioral experiments and patch-clamp recordings of spontaneous, miniature and dorsal root stimulation-evoked excitatory postsynaptic currents (sEPSCs, mEPSCs, eEPSCs) from superficial dorsal horn neurons in acute rat spinal cord slices were used. The intrathecal application of CCL2 induced thermal hyperalgesia and mechanical allodynia, while pretreatment with the TRPV1 receptor antagonist SB366791 diminished the thermal but not the mechanical hypersensitivity. Patch-clamp experiments showed an increase of sEPSC and mEPSC (124.5 ± 12.8% and 161.2 ± 17.3%, respectively) frequency in dorsal horn neurons after acute CCL2 application. This CCL2-induced increase was prevented by SB366791 pretreatment (89.4 ± 6.0%, 107.5 ± 14.2%). CCL2 application increased the amplitude of eEPSCs (188.1 ± 32.1%); this increase was significantly lower in experiments with SB366791 pretreatment (120.8 ± 17.2%). Our results demonstrate that the activation of spinal TRPV1 receptors plays an important role in the modulation of nociceptive signaling induced by CCL2 application. The mechanisms of cooperation between the CCL2 activated receptors and TRPV1 receptors on the central branches of primary afferent fibers may be especially important during different pathological pain states and need to be further investigated.
Department of Functional Morphology, Institute of Physiology vvi, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic. Electronic address: dianaspicarova@biomed.cas.cz.
Diana
D
Spicarova
Department of Functional Morphology, Institute of Physiology vvi, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic. Electronic address: adamek@biomed.cas.cz.
Pavel
P
Adamek
Department of Functional Morphology, Institute of Physiology vvi, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic. Electronic address: kalynovska@biomed.cas.cz.
Nataliia
N
Kalynovska
Department of Functional Morphology, Institute of Physiology vvi, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic. Electronic address: skya@biomed.cas.cz.
Petra
P
Mrozkova
Department of Functional Morphology, Institute of Physiology vvi, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic. Electronic address: palecek@biomed.cas.cz.
Jiri
J
Palecek
D000813:Anilides / Q000627:therapeutic use; D000818:Animals; D000831:Animals, Newborn; D002211:Capsaicin / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000633:toxicity*; D002934:Cinnamates / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism*; D066298:In Vitro Techniques; D048748:MAP Kinase Kinase Kinase 3 / Q000378:metabolism; D008297:Male; D017288:Pain Threshold / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D020671:Posterior Horn Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018689:Sensory System Agents / Q000494:pharmacology; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors
D000813:Anilides; D018932:Chemokine CCL2; D002934:Cinnamates; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; D018689:Sensory System Agents; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D048748:MAP Kinase Kinase Kinase 3; D002211:Capsaicin
CCL2; EPSC; Pain; Spinal cord; Synaptic transmission; TRPV1