Increased Chemokine Signaling in a Model of HIV1-Associated Peripheral Neuropathy

Abstract

Painful distal sensory polyneuropathy (DSP) is the most common neurological complication of HIV1 infection. Although infection with the virus itself is associated with an incidence of DSP, patients are more likely to become symptomatic following initiation of nucleoside reverse transcriptase inhibitor (NRTI) treatment. The chemokines monocyte chemoattractant protein-1 (MCP1/CCL2) and stromal derived factor-1 (SDF1/CXCL12) and their respective receptors, CCR2 and CXCR4, have been implicated in HIV1 related neuropathic pain mechanisms including NRTI treatment in rodents. Utilizing a rodent model that incorporates the viral coat protein, gp120, and the NRTI, 2'3'-dideoxycytidine (ddC), we examined the degree to which chemokine receptor signaling via CCR2 and CXCR4 potentially influences the resultant chronic hypernociceptive behavior. We observed that following unilateral gp120 sciatic nerve administration, rats developed profound tactile hypernociception in the hindpaw ipsilateral to gp120 treatment. Behavioral changes were also present in the hindpaw contralateral to the injury, albeit delayed and less robust. Using immunohistochemical studies, we demonstrated that MCP1 and CCR2 were upregulated by primary sensory neurons in lumbar ganglia by post-operative day (POD) 14. The functional nature of these observations was confirmed using calcium imaging in acutely dissociated lumbar dorsal root ganglion (DRG) derived from gp120 injured rats at POD 14. Tactile hypernociception in gp120 treated animals was reversed following treatment with a CCR2 receptor antagonist at POD 14. Some groups of animals were subjected to gp120 sciatic nerve injury in combination with an injection of ddC at POD 14. This injury paradigm produced pronounced bilateral tactile hypernociception from POD 14–48. More importantly, functional MCP1/CCR2 and SDF1/CXCR4 signaling was present in sensory neurons. In contrast to gp120 treatment alone, the hypernociceptive behavior associated with the injury plus drug combination was only effectively reversed using the CXCR4 antagonist AMD3100. These studies indicate that the functional upregulation of CCR2 and CXCR4 signaling systems following a combination of gp120 and an NRTI are likely to be of central importance to associated DSP and may serve as potential therapeutic targets for treatment of this syndrome.

CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis

“…This process has been demonstrated on cultured (18) and previously injured adult DRG sensory neurons (27,(29)(30)(31)(32). In addition, chemokines are of central importance in the recruitment of leukocytes.…”

“…These models included chronic constriction injury (26), unilateral gp120 sciatic nerve administration (27), partial ligation of the sciatic nerve (28), and focal nerve demyelination (29). Mechanical allodynia after nerve injury has been reported to be inhibited by treatment with a CCR2 receptor antagonist (27,29), and Ccr2-null mice were protected from mechanical allodynia after nerve injury but not during acute inflammatory pain tests (21). We find here that Ccr2-null mice initially develop mechanical allodynia (first phase), but it resolves in the absence of MCP-1/CCR2 signaling.…”

“…In brief, MCP-1 was applied for 3 min by adding 1 mL of solution directly to the bath chamber. Cells were washed 3 min before applying positive control solution (potassium, 50 mM) (27). Three independent experiments each using DRG pooled from three to four mice were performed.…”

Upregulation of Chemokine CXCL12 in the Dorsal Root Ganglia and Spinal Cord Contributes to the Development and Maintenance of Neuropathic Pain Following Spared Nerve Injury in Rats

“…Increasing evidence suggests that CXCL12/CXCR4 play important roles in nociceptive signal processing [11][12][13][14]. They are widely distributed and constitutively expressed in small amounts in small-and medium-sized dorsal root ganglia (DRG) neurons and glia (satellite cells) and in the spinal cord [15,16]. The administration of antiretroviral drugs or unilateral chronic constriction injury of the sciatic nerve leads to the development of neuropathic pain, which is correlated with the upregulation of both CXCL12 and CXCR4 in the DRG [17,18].…”

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

“…Similar up-regulation was found in previous studies using other rodent models for neuropathic pain in the DRG or TG. These models included unilateral application of glycoprotein 120 into the sciatic nerve, 27 chronic constriction injury, 28 partial ligation of the sciatic nerve, 29 focal nerve demyelination, 30 and experimental osteoarthritis. 16 However, the change rhythms in CCL2 expression were different in some cases.…”