Chemokine CCL2 and its receptor CCR2 in the medullary dorsal horn are involved in trigeminal neuropathic pain

Abstract

BackgroundNeuropathic pain in the trigeminal system is frequently observed in clinic, but the mechanisms involved are largely unknown. In addition, the function of immune cells and related chemicals in the mechanism of pain has been recognized, whereas few studies have addressed the potential role of chemokines in the trigeminal system in chronic pain. The present study was undertaken to test the hypothesis that chemokine C-C motif ligand 2 (CCL2)-chemokine C-C motif receptor 2 (CCR2) signaling in the trigeminal nucleus is involved in the maintenance of trigeminal neuropathic pain.MethodsThe inferior alveolar nerve and mental nerve transection (IAMNT) was used to induce trigeminal neuropathic pain. The expression of ATF3, CCL2, glial fibrillary acidic protein (GFAP), and CCR2 were detected by immunofluorescence histochemical staining and western blot. The cellular localization of CCL2 and CCR2 were examined by immunofluorescence double staining. The effect of a selective CCR2 antagonist, RS504393 on pain hypersensitivity was checked by behavioral testing.ResultsIAMNT induced persistent (>21 days) heat hyperalgesia of the orofacial region and ATF3 expression in the mandibular division of the trigeminal ganglion. Meanwhile, CCL2 expression was increased in the medullary dorsal horn (MDH) from 3 days to 21 days after IAMNT. The induced CCL2 was colocalized with astroglial marker GFAP, but not with neuronal marker NeuN or microglial marker OX-42. Astrocytes activation was also found in the MDH and it started at 3 days, peaked at 10 days and maintained at 21 days after IAMNT. In addition, CCR2 was upregulated by IAMNT in the ipsilateral medulla and lasted for more than 21 days. CCR2 was mainly colocalized with NeuN and few cells were colocalized with GFAP. Finally, intracisternal injection of CCR2 antagonist, RS504393 (1, 10 μg) significantly attenuated IAMNT-induced heat hyperalgesia.ConclusionThe data suggest that CCL2-CCR2 signaling may be involved in the maintenance of orofacial neuropathic pain via astroglial–neuronal interaction. Targeting CCL2-CCR2 signaling may be a potentially important new treatment strategy for trigeminal neuralgia.

Expression and function of CCL2/CCR2 in rat micturition reflexes and somatic sensitivity with urinary bladder inflammation

“…Our laboratory and others have previously demonstrated chemokine/ receptor expression (CX3CL1/CX3CR1; CXCL12/CXCR4) (5, 68, 79) and function (CXCL12/CXCR4) (5) associated with urinary bladder inflammation. These results extend previous findings (20,65,76,80,81) by demonstrating that CCL2/CCR2 interactions contribute to inflammation-induced bladder dysfunction and increased referred somatic sensitivity. These studies provide additional support for chemokines/receptors as potential lower urinary tract targets with therapeutic potential in the context of urinary bladder inflammation.…”

“…To evaluate the effects of CCR2 blockade on bladder function, rats were anesthetized (1-2% isoflurane) and saline or RS504393 (5 M), a highly specific CCR2 receptor antagonist (7,37,81), was intravesically infused for 30 min. Prior to intravesical drug infusion, the bladder was manually emptied using the Credé maneuver.…”

“…Micturition function before and after vehicle or RS504393 intravesical instillation was evaluated in the same rats (control and 4-h CYP-induced cystitis). A variety of routes of administration and concentrations of RS504393 have been used in diverse applications (7,37,81). Thus, the concentration used in the present study was based on published studies (7,37,81) but was also determined empirically in pilot studies.…”

Emerging targets in neuroinflammation-driven chronic pain

“…First, nerve injury in mice induces expression of CCL2 astrocytes in the spinal cord and trigeminal nucleus and also upregulates CCR2 in spinal cord neurons 54, 80 . Second, incubation of spinal cord slices with CCL2 very rapidly (within minutes) increases excitatory synaptic transmission, NMDA currents and ERK activation in dorsal horn neurons 54 .…”

Chemokine ligand 2 in the trigeminal ganglion regulates pain induced by experimental tooth movement

“…6 Although it is almost absent from the normal central nervous system, expression of CCL2 in the spinal cord could be induced following ischemia, neural trauma, and inflammation. [7][8][9][10][11] Similar up-regulation of CCL2 has also been found in the dorsal root ganglion (DRG) subjected to peripheral nerve injury. [12][13][14] A growing amount of evidence has demonstrated that the CCL2/CCR2 axis might play an essential role in neuropathic pain.…”