Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat: a mechanism for the development of chronic sensitization of peripheral nociceptors

Sonia Bhangoo, Dongjun Ren, Richard J Miller, Kenneth J Henry, Jayana Lineswala, Chafiq Hamdouchi, Baolin Li, Patrick E Monahan, David M Chan, Matthew S Ripsch, Fletcher A White, Sonia Bhangoo, Dongjun Ren, Richard J Miller, Kenneth J Henry, Jayana Lineswala, Chafiq Hamdouchi, Baolin Li, Patrick E Monahan, David M Chan, Matthew S Ripsch, Fletcher A White

Abstract

Background: Animal and clinical studies have revealed that focal peripheral nerve axon demyelination is accompanied by nociceptive pain behavior. C-C and C-X-C chemokines and their receptors have been strongly implicated in demyelinating polyneuropathies and persistent pain syndromes. Herein, we studied the degree to which chronic nociceptive pain behavior is correlated with the neuronal expression of chemokines and their receptors following unilateral lysophosphatidylcholine (LPC)-induced focal demyelination of the sciatic nerve in rats.

Results: Focal nerve demyelination increased behavioral reflex responsiveness to mechanical stimuli between postoperative day (POD) 3 and POD28 in both the hindpaw ipsilateral and contralateral to the nerve injury. This behavior was accompanied by a bilateral increase in the numbers of primary sensory neurons expressing the chemokine receptors CCR2, CCR5, and CXCR4 by POD14, with no change in the pattern of CXCR3 expression. Significant increases in the numbers of neurons expressing the chemokines monocyte chemoattractant protein-1 (MCP-1/CCL2), Regulated on Activation, Normal T Expressed and Secreted (RANTES/CCL5) and interferon gamma-inducing protein-10 (IP-10/CXCL10) were also evident following nerve injury, although neuronal expression pattern of stromal cell derived factor-1alpha (SDF1/CXCL12) did not change. Functional studies demonstrated that acutely dissociated sensory neurons derived from LPC-injured animals responded with increased [Ca2+]i following exposure to MCP-1, IP-10, SDF1 and RANTES on POD 14 and 28, but these responses were largely absent by POD35. On days 14 and 28, rats received either saline or a CCR2 receptor antagonist isomer (CCR2 RA-[R]) or its inactive enantiomer (CCR2 RA-[S]) by intraperitoneal (i.p.) injection. CCR2 RA-[R] treatment of nerve-injured rats produced stereospecific bilateral reversal of tactile hyperalgesia.

Conclusion: These results suggest that the presence of chemokine signaling by both injured and adjacent, uninjured sensory neurons is correlated with the maintenance phase of a persistent pain state, suggesting that chemokine receptor antagonists may be an important therapeutic intervention for chronic pain.

Figures

Figure 1
Figure 1
Mean threshold force required for paw withdrawal to Von Frey stimulation at 1, 3, 7, 14, 21, 28, 35 and 42 days following LPC-induced focal nerve demyelination. Each data point is the mean threshold (± SE) force on the hindpaw ipsilateral (black circle) or contralateral (white circle) to the focal nerve injury site eliciting a withdrawal response (n = 10). Reduced behavioral thresholds for the hindpaw ipsilateral to the nerve lesion were significantly different from pre-operative baseline on postoperative days 1–28. The threshold force for the hindpaw contralateral to the nerve lesion did not reach significance until postoperative day 3, and significant differences were observed until postoperative day 28. The time course of sham injury (n = 6) is also represented but did not differ from the uninjured animals. Analysis was performed using two-way ANOVA followed by the Bonferroni post-hoc pair-wise comparisons (*p B) LPC-induced focal nerve demyelination did not produce changes in thermal responses as assessed by the Hargreaves test. Each bar is the mean withdrawal latency (± SE) of the hindpaw ipsilateral (white bar) or contralateral (black bar) to the focal nerve demyelination injury at postoperative day 7 and 14 (n = 10).
Figure 2
Figure 2
Expression of CCR2 mRNA and protein immunoreactivity in rat lumbar DRG ipsilateral to focal nerve demyelination. A) Lumbar DRG removed from vehicle-treated animals at POD7 did not exhibit CCR2 mRNA expression (n = 5). B) Many lumbar DRG neurons in vehicle-treated rats sensory neurons were positive for isolectin IB4, a neuronal phenotype that distinguishes some C-fiber nociceptors (green cells). There was no evidence of CCR2 protein expression in sham animals (n = 5). C) Lumbar DRG neurons from nerve-injured rats on POD7 exhibited CCR2 mRNA transcripts in some small and medium diameter neurons (black arrows). Open black arrowhead indicates a neuron without CCR2 mRNA transcripts (n = 4). D) Lumbar DRG neurons from a rat subjected to focal nerve demyelination exhibited few CCR2 immunopositive (white arrows) sensory neurons (n = 4). E) Many lumbar DRG neurons on POD14 exhibited CCR2 mRNA transcripts (black arrows). Open arrowhead indicates non-labeled neuron. F) CCR2 immunoreactivity was present in an increased number of neurons at POD14 (white arrows; n = 5). Scale bar is; 30 μm (A, C), 50 μm (B, D, F), and 100 μm (E).
Figure 3
Figure 3
Percentage of MCP-1, CCR2 and IP-10 immunoreactive neurons with IB4-positive neuronal profiles on POD 14. MCP-1 expression was increased by LPC-induced nerve injury within the IB4-labeled neuronal group in both the DRG ipsilateral and contralateral to the nerve injury. Sham-injury treatment did not produce significant changes in the extent of MCP-1/IB4 colocalization. CCR2 expression was increased by LPC-induced nerve injury within IB4-labeled neuronal group in both the DRG ipsilateral and contralateral to the nerve injury. Like, MCP-1, sham-injury treatment did not produce significant changes in CCR2/IB4 colocalization in either DRG ipsi- or contralateral to the sham injury. IP-10 expression was increased by LPC-induced nerve injury within IB4-labelled neuronal group in both the DRG ipsilateral and contralateral to the nerve injury, while sham-injury treatment did not produce significant changes in IP-10/IB4 colocalization. Comparisons of immunoreactive cell percentages were made between LPC-treatment and sham-treated animals. Data represent means ± SE. Analysis was performed using two-way ANOVA followed by the Bonferroni post-hoc pair-wise comparisons (*p < 0.01).
Figure 4
Figure 4
Expression of CXCR4 mRNA in rat lumbar DRG ipsilateral to focal nerve demyelination. Low (A) and high power (C) photomicrographs of CXCR4 mRNA transcripts present in lumbar DRG removed from vehicle-treated rodents at POD14 (n = 3). Many non-neuronal cells strongly expressed CXCR4. (C) Some presumptive neurons expressed low levels of CXCR4 mRNA (white arrow). Low (B) and high power (D) photomicrographs of CXCR4 mRNA transcripts present in lumbar DRGs derived from injured rats at POD14 (n = 4). The expression level and number of non-neuronal cells exhibiting CXCR4 mRNA transcripts in the lumbar DRG did not change following focal nerve demyelination. However, many neurons upregulated CXCR4 mRNA expression (D; white arrows indicate neurons with low levels of mRNA transcripts; white arrowhead points to a neuron lacking CXCR4 mRNA expression). (Scale bar is 1 mm (A and B); 40 μm (C and D).
Figure 5
Figure 5
Expression of CXCR3 and CCR5 mRNA in rat lumbar DRG following focal nerve demyelination. (A) Many sensory neurons in the lumbar DRG removed from vehicle-treated rats exhibited CXCR3 mRNA transcripts at POD14 (n = 3). (B) CCR5 mRNA expression was absent from the lumbar DRG of vehicle-treated rats at POD14 (n = 3). (C) CXCR3 mRNA expression patterns in sensory neurons subjected to focal nerve demyelination did not differ from vehicle-treated rodents at POD14 (n = 4), but there was an increase in the intensity of CXCR3 mRNA expression. (D) Many neurons in the injured rat lumbar DRG expressed CCR5 transcripts at POD14 (n = 4). Scale bar is 250 μm (A and C); 100 μm (B and D).
Figure 6
Figure 6
Colocalization of MCP-1 immunoreactivity (ir) and isolectin B4(IB4)-binding in the lumbar DRG ipsilateral to LPC-induced demyelination injury at POD7. IB4-binding in rat DRG neurons distinguishes C-fiber nociceptors. (A) Naïve rat lumbar DRG were completely negative for MCP-1ir. (B) Lumbar DRG ipsilateral to LPC-induced sciatic nerve injury exhibited numerous small diameter neurons that are MCP-1 positive at POD7 (red arrows). (C) Numerous small IB4-binding presumptive nociceptors are present in the same DRG tissue section (green arrows). (D) Merging panels B and C demonstrates the extent of colocalization present in lumbar DRG tissue section (yellow arrows). Note not all MCP-1ir neurons were positive for IB4 at POD7 (red arrow). Scale bar is 100 μm (A, B, C and D).
Figure 7
Figure 7
Expression of RANTES mRNA in rat lumbar DRG following focal nerve demyelination. (A) RANTES mRNA expression was absent from the lumbar DRG of vehicle-treated rats at POD14 (n = 3). (B) Many sensory neurons in the DRG ipsilateral to the nerve injury at POD 14 were positive for RANTES mRNA (C) Numerous sensory neurons in the DRG contralateral to the nerve injury displayed expression of RANTES mRNA, albeit at a lower level when compared with the DRG ipsilateral to the nerve injury. Scale bar is 250 μm (A and C); 100 μm (B and D).
Figure 8
Figure 8
Colocalization of IP-10 immunoreactivity (-ir) and isolectin B4 (IB4)-binding neurons in the lumbar DRG of naïve rat and rats subjected to LPC-induced nerve injury. IB4-binding in rat DRG neurons distinguishes a population of C-fiber nociceptors. A) The majority of IP-10-ir cells were limited to medium diameter neurons in the lumbar DRG from vehicle-treated rats (red arrows). D) IB4-binding small diameter presumptive nociceptors (green arrows) did not colocalize with IP-10-ir lumbar DRG neurons from vehicle-treated rodents at POD7 (G, merged images). B) Lumbar DRG ipsilateral to focal nerve demyelination exhibited numerous medium and small diameter IP-10-ir neurons at POD7. Limited numbers of neurons were positive for both IP-10-ir (B, red arrows) and IB4-binding (E, green arrows) on POD7 (H, merged images). C) Many IP-10-ir neurons (red arrows) colocalized with IB4-binding neurons (F, green arrows) at POD14 (I, merged images). Yellow arrows indicate colocalized cells. Scale bar is 100 μm.
Figure 9
Figure 9
Chemokines increased [Ca2+]i levels in acutely isolated rat DRG cells following focal demyelination injury. The figure shows examples of responses of cells acutely isolated from rat DRGs ipsilateral to the nerve injury at various days after a focal demyelination injury. Under normal conditions, cells rarely respond to any chemokine but did respond to other stimuli such as high K or ATP (A). However, there was an increased responsiveness of the cells, the majority of which could be characterized as neurons, between post-operative days 14–28 (B and C, respectively). The frequency of the responses to chemokines returned to approximately the same level as control animals by post-operative day 35 (D). For all experiments, MCP-1 (M), IP-10 (I), RANTES (R), SDF1 (S) were applied at a concentration of 100 nM. Capsaicin (C), high K (K) and ATP (A) were applied at concentrations of 100 nM, 50 mM and 100 uM, respectively.
Figure 10
Figure 10
CCR2 receptor antagonist (CCR2 RA-[R]) administration reversed existing nociceptive behavior. Animals were subjected to a nerve demyelination injury on day 0 and nociceptive behavior was assessed for 28 days. On days 14 and 28 post-surgery, animals received 5 mg/kg CCR2 RA-[R] or 5 mg/kg of its inactive enantiomer, (CCR2 RA-[S], or saline by intraperitoneal injection, and behavioral responses were tested 1 h later. Administration of the CCR2 RA-[R] to focal nerve demyelination injured rats resulted in a significant bilateral increase of mN force required to elicit a paw withdrawal compared with vehicle-treated controls and animals subjected to CCR2 RA-[S]. Nociceptive behavior in vehicle-treated controls and animals subjected to CCR2 RA-[S] differed significantly from day 0 pre-injury baseline responses (*p < 0.01). Data represent means ± SE.

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