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Increased chemokine signaling in a model of HIV1-associated peripheral neuropathy.

Bhangoo SK, Ripsch MS, Buchanan DJ, Miller RJ, White FA - Mol Pain (2009)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Pharmacology, Northwestern University, Chicago, IL, USA. bhangoos@nidcr.nih.gov

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.

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Mechanical and thermal behavioral responses following perineural gp120/hCD4 treatment alone or in combination with a single 25 mg/kg i.p injection of 2'-3'-dideoxycytidine. A) Rats were assessed for low-threshold mechanical sensitivity (von Frey test) at 3, 7, 10, 14, 17, 28 days following perineural gp120/hCD4 treatment. Reduced behavioral thresholds for the hindpaw ipsilateral to the nerve lesion (black square) were significantly different from pre-operative baseline from post-operative day (POD) 3–28. The threshold force for the hindpaw contralateral to the nerve lesion (black diamond), did not meet the pre-determined criteria indicative of mechanical hypernociceptive behavior until POD17. The time course of sham injury did not differ from the uninjured animals (ipsilateral sham, black circle; contralateral sham, black triangle). (n = 10; * p < 0.01). POD: post-operative day after gp120/hCD4 treatment. B) Mean threshold force required for paw withdrawal to Von Frey stimulation following perineural gp120/hCD4 treatment and a single 25 mg/kg i.p injection of 2'-3'-dideoxycytidine (ddC; n = 10). The ddC injection was given on POD14 after gp120 treatment. Reduced behavioral thresholds for the hindpaw ipsilateral (black square) and contralateral (black diamond) to the nerve treatment were seen as early as POD17/post-injection day (PID) 3 and reached the lowest levels by POD21/PID7 (p < 0.01). The time course of sham injury did not differ from the uninjured animals (ipsilateral sham, black circle; contralateral sham, black triangle). C) gp120/hCD4 induced nerve injury 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 nerve injury at POD 7 and 14 (n = 10). After a single i.p. injection of ddC at POD 14, thermal hyperalgesia was observed as early as PID 3 and reached the shortest latency by PID7 in the paws ipsilateral and contralateral to the gp120/hCD4 treatment. POD: post-operative day after gp120/hCD4 treatment; PID: post-injection day after ddc treatment. (n = 10; *p < .05).
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Figure 1: Mechanical and thermal behavioral responses following perineural gp120/hCD4 treatment alone or in combination with a single 25 mg/kg i.p injection of 2'-3'-dideoxycytidine. A) Rats were assessed for low-threshold mechanical sensitivity (von Frey test) at 3, 7, 10, 14, 17, 28 days following perineural gp120/hCD4 treatment. Reduced behavioral thresholds for the hindpaw ipsilateral to the nerve lesion (black square) were significantly different from pre-operative baseline from post-operative day (POD) 3–28. The threshold force for the hindpaw contralateral to the nerve lesion (black diamond), did not meet the pre-determined criteria indicative of mechanical hypernociceptive behavior until POD17. The time course of sham injury did not differ from the uninjured animals (ipsilateral sham, black circle; contralateral sham, black triangle). (n = 10; * p < 0.01). POD: post-operative day after gp120/hCD4 treatment. B) Mean threshold force required for paw withdrawal to Von Frey stimulation following perineural gp120/hCD4 treatment and a single 25 mg/kg i.p injection of 2'-3'-dideoxycytidine (ddC; n = 10). The ddC injection was given on POD14 after gp120 treatment. Reduced behavioral thresholds for the hindpaw ipsilateral (black square) and contralateral (black diamond) to the nerve treatment were seen as early as POD17/post-injection day (PID) 3 and reached the lowest levels by POD21/PID7 (p < 0.01). The time course of sham injury did not differ from the uninjured animals (ipsilateral sham, black circle; contralateral sham, black triangle). C) gp120/hCD4 induced nerve injury 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 nerve injury at POD 7 and 14 (n = 10). After a single i.p. injection of ddC at POD 14, thermal hyperalgesia was observed as early as PID 3 and reached the shortest latency by PID7 in the paws ipsilateral and contralateral to the gp120/hCD4 treatment. POD: post-operative day after gp120/hCD4 treatment; PID: post-injection day after ddc treatment. (n = 10; *p < .05).

Mentions: After establishing a baseline behavioral assessment, rats were treated with a perineural application of either vehicle (saline), or gp120/hCD4 in saline (n = 6–8/group). Rats treated with gp120/hCD4 displayed mechanical hypernociception (-20 mN change in PWT) as measured by graded von Frey filaments in the limb ipsilateral to the injury by POD 5 (Fig. 1A; n = 10, p < 0.001) and in the limb contralateral to the injury by POD 17 (Fig. 1A; n = 10, p < 0.01). The force required to elicit a PWT remained significantly below baseline thresholds until POD 28 for the hindpaw contralateral to the lesion and POD 35 for the hindpaw ipsilateral to the injury. Vehicle treated sham operated rodents did not exhibit a PWT decrease that was significant at any time point (Fig. 1A). Upon completion of testing, rats were euthanized and tissues utilized for further analysis.


Increased chemokine signaling in a model of HIV1-associated peripheral neuropathy.

Bhangoo SK, Ripsch MS, Buchanan DJ, Miller RJ, White FA - Mol Pain (2009)

Mechanical and thermal behavioral responses following perineural gp120/hCD4 treatment alone or in combination with a single 25 mg/kg i.p injection of 2'-3'-dideoxycytidine. A) Rats were assessed for low-threshold mechanical sensitivity (von Frey test) at 3, 7, 10, 14, 17, 28 days following perineural gp120/hCD4 treatment. Reduced behavioral thresholds for the hindpaw ipsilateral to the nerve lesion (black square) were significantly different from pre-operative baseline from post-operative day (POD) 3–28. The threshold force for the hindpaw contralateral to the nerve lesion (black diamond), did not meet the pre-determined criteria indicative of mechanical hypernociceptive behavior until POD17. The time course of sham injury did not differ from the uninjured animals (ipsilateral sham, black circle; contralateral sham, black triangle). (n = 10; * p < 0.01). POD: post-operative day after gp120/hCD4 treatment. B) Mean threshold force required for paw withdrawal to Von Frey stimulation following perineural gp120/hCD4 treatment and a single 25 mg/kg i.p injection of 2'-3'-dideoxycytidine (ddC; n = 10). The ddC injection was given on POD14 after gp120 treatment. Reduced behavioral thresholds for the hindpaw ipsilateral (black square) and contralateral (black diamond) to the nerve treatment were seen as early as POD17/post-injection day (PID) 3 and reached the lowest levels by POD21/PID7 (p < 0.01). The time course of sham injury did not differ from the uninjured animals (ipsilateral sham, black circle; contralateral sham, black triangle). C) gp120/hCD4 induced nerve injury 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 nerve injury at POD 7 and 14 (n = 10). After a single i.p. injection of ddC at POD 14, thermal hyperalgesia was observed as early as PID 3 and reached the shortest latency by PID7 in the paws ipsilateral and contralateral to the gp120/hCD4 treatment. POD: post-operative day after gp120/hCD4 treatment; PID: post-injection day after ddc treatment. (n = 10; *p < .05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2734548&req=5

Figure 1: Mechanical and thermal behavioral responses following perineural gp120/hCD4 treatment alone or in combination with a single 25 mg/kg i.p injection of 2'-3'-dideoxycytidine. A) Rats were assessed for low-threshold mechanical sensitivity (von Frey test) at 3, 7, 10, 14, 17, 28 days following perineural gp120/hCD4 treatment. Reduced behavioral thresholds for the hindpaw ipsilateral to the nerve lesion (black square) were significantly different from pre-operative baseline from post-operative day (POD) 3–28. The threshold force for the hindpaw contralateral to the nerve lesion (black diamond), did not meet the pre-determined criteria indicative of mechanical hypernociceptive behavior until POD17. The time course of sham injury did not differ from the uninjured animals (ipsilateral sham, black circle; contralateral sham, black triangle). (n = 10; * p < 0.01). POD: post-operative day after gp120/hCD4 treatment. B) Mean threshold force required for paw withdrawal to Von Frey stimulation following perineural gp120/hCD4 treatment and a single 25 mg/kg i.p injection of 2'-3'-dideoxycytidine (ddC; n = 10). The ddC injection was given on POD14 after gp120 treatment. Reduced behavioral thresholds for the hindpaw ipsilateral (black square) and contralateral (black diamond) to the nerve treatment were seen as early as POD17/post-injection day (PID) 3 and reached the lowest levels by POD21/PID7 (p < 0.01). The time course of sham injury did not differ from the uninjured animals (ipsilateral sham, black circle; contralateral sham, black triangle). C) gp120/hCD4 induced nerve injury 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 nerve injury at POD 7 and 14 (n = 10). After a single i.p. injection of ddC at POD 14, thermal hyperalgesia was observed as early as PID 3 and reached the shortest latency by PID7 in the paws ipsilateral and contralateral to the gp120/hCD4 treatment. POD: post-operative day after gp120/hCD4 treatment; PID: post-injection day after ddc treatment. (n = 10; *p < .05).
Mentions: After establishing a baseline behavioral assessment, rats were treated with a perineural application of either vehicle (saline), or gp120/hCD4 in saline (n = 6–8/group). Rats treated with gp120/hCD4 displayed mechanical hypernociception (-20 mN change in PWT) as measured by graded von Frey filaments in the limb ipsilateral to the injury by POD 5 (Fig. 1A; n = 10, p < 0.001) and in the limb contralateral to the injury by POD 17 (Fig. 1A; n = 10, p < 0.01). The force required to elicit a PWT remained significantly below baseline thresholds until POD 28 for the hindpaw contralateral to the lesion and POD 35 for the hindpaw ipsilateral to the injury. Vehicle treated sham operated rodents did not exhibit a PWT decrease that was significant at any time point (Fig. 1A). Upon completion of testing, rats were euthanized and tissues utilized for further analysis.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Pharmacology, Northwestern University, Chicago, IL, USA. bhangoos@nidcr.nih.gov

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.

Show MeSH
Related in: MedlinePlus