Force-Dependent Development of Neuropathic Central Pain and Time-Related CCL2/CCR2 Expression after Graded Spinal Cord Contusion Injuries of the Rat

Abstract

Spinal cord injury (SCI) often results in intractable chronic central pain syndromes. Recently chemokines such as CCL2 were identified as possible key integrators of neuropathic pain and inflammation after peripheral nerve lesion. The focus of the current study was the investigation of time-dependent CCL2 and CCR2 expression in relation to central neuropathic pain development after spinal cord impact lesions of 100, 150, or 200 kdyn force on spinal cord level T9 in adult rats. Below-level pain was monitored with weekly sensory testing for 42 days after SCI. In parallel expression of CCL2/CCR2 on cervical, thoracic, and lumbar levels was investigated by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry early (7 days [7d]), intermediate (15d), and late (42d) after lesion. Cellular source and anatomical pain related expression was determined by double-immunohistochemistry. Force-defined SCI led to acute mechanical hypersensitivity in all lesion groups, and to persistent below-level pain in severely injured animals. While in the early post-operative time course, CCL2 and CCR2 were expressed in astroglia and granulocytes only on level T9; there was additional astroglial CCL2 expression in dorsal columns and dorsal horns above and below T9 of severely injured animals 42d after lesion. In dorsal horns (level L3-L5) of animals exhibiting chronic below-level pain CCL2 was co-expressed with transmitters and receptors that are involved in nociceptive processing like calcitonin gene-related peptide (CGRP), Substance-P, vanilloid-receptor-1, and its activated phosphorylated form. These data demonstrate lesion grade dependence of below-level pain development and suggest chemokines as potential candidates for integrating inflammation and central neuropathic pain after SCI.

Curcumin Inhibits LPS-Induced CCL2 Expression via JNK Pathway in C6 Rat Astrocytoma Cells

“…Astrocytes, however, appear to be the primary producers of CCL2 in pathological conditions, such as experimental autoimmune encephalomyelitis (Berman et al 1996;McManus et al 1998;Van Der Voorn et al 1999), brain ischemia (Kim et al 1995;Che et al 2001), traumatic brain damage (Glabinski et al 1996), and Alzheimer's disease (Johnstone et al 1999). In addition, the expression of CCL2 is upregulated in spinal astrocytes after spinal nerve ligation (Gao et al 2009) and spinal cord contusion injuries (Knerlich-Lukoschus et al 2008). In vitro studies also support the production of CCL2 by primary cultured astrocytes (Croitoru-Lamoury et al 2003;Meeuwsen et al 2003;Mojsilovic-Petrovic et al 2007;Gao et al 2009).…”

MCP-1 stimulates spinal microglia via PI3K/Akt pathway in bone cancer pain

“…Indeed, MCP-1 has been found to be secreted by primary afferent neurons (Dansereau et al, 2008;Zhang and De Koninck, 2006) and astrocytes (Gao et al, 2009;Knerlich-Lukoschus et al, 2008). CCR2 has also been found to be expressed in response to neuropathic pain by various cell types in the spinal cord, including microglia (Abbadie et al, 2003), astrocytes (KnerlichLukoschus et al, 2008), and neurons (Gao et al, 2009;Gosselin et al, 2005).…”

Dendritic spine dysgenesis in neuropathic pain

“…Injuries, such as SCI or peripheral nerve injury, increase glutamate signaling, release of neuromodulator substance-P, and neurotrophic factors, i.e., BDNF. The signaling of these molecules operates downstream through an elevation of intracellular calcium, which consequently leads to synaptic potentiation [15,29,34,36]. Taken together, synaptic reorganization in spinal cord pain circuitry is a well-known phenomenon that can partially explain central sensitization (i.e., amplified excitability of neurons and circuits in nociceptive pathways) associated with neuropathic pain [33].…”