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The differential effect of intrathecal Nav1.8 blockers on the induction and maintenance of capsaicin- and peripheral ischemia-induced mechanical allodynia and thermal hyperalgesia.
Anesth Analg. 2012 Jan; 114(1):215-23.A&A

Abstract

BACKGROUND

It has been reported that the selective blockade of Nav1.8 sodium channels could be a possible target for the development of analgesics without unwanted side effects. However, the precise role of spinal Nav1.8 in the induction and maintenance of persistent pain, e.g., mechanical allodynia (MA) and thermal hyperalgesia (TH), is not clear. We designed this study to investigate whether spinal Nav1.8 contributes to capsaicin-induced and peripheral ischemia-induced MA and TH.

METHODS

The Nav1.8 blockers, A-803467 or ambroxol, were injected intrathecally either before or after intraplantar capsaicin injection. To evaluate capsaicin-induced neuronal activation in the spinal cord, we quantified the number of Fos-immunoreactive cells in the dorsal horn. In the thrombus-induced ischemic pain model, we determined the differential effect of A-803467 on the induction phase or maintenance phase of MA.

RESULTS

Intrathecal injection of A-803467 (10, 30, 100 nmol) or ambroxol (241, 724, 2410 nmol) before intraplantar injection of capsaicin dose dependently prevented the induction of both MA and TH. However, posttreatment with A-803467 (100 nmol) and ambroxol (2410 nmol) did not reduce the MA that had already developed, but did significantly suppress capsaicin-induced TH. Moreover, the capsaicin-induced increase of spinal Fos-immunoreactive cells was significantly diminished by pretreatment, but not posttreatment with Nav1.8 blockers. In thrombus-induced ischemic pain rats, repetitive treatments of A-803467 during the induction period also prevented the development of MA, whereas A-803467 treatments during the maintenance period were ineffective in preventing or reducing MA.

CONCLUSIONS

These results demonstrate that spinal activation of Nav1.8 mediates the early induction of MA, but not the maintenance of MA. However, both the induction and maintenance of TH are modulated by the intrathecal injection of Nav1.8 blockers. These findings suggest that early treatment with a Nav1.8 blocker can be an important factor in the clinical management of chronic MA associated with inflammatory and ischemic pain.

Authors+Show Affiliations

Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, South Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22127815

Citation

Moon, Ji-Young, et al. "The Differential Effect of Intrathecal Nav1.8 Blockers On the Induction and Maintenance of Capsaicin- and Peripheral Ischemia-induced Mechanical Allodynia and Thermal Hyperalgesia." Anesthesia and Analgesia, vol. 114, no. 1, 2012, pp. 215-23.
Moon JY, Song S, Yoon SY, et al. The differential effect of intrathecal Nav1.8 blockers on the induction and maintenance of capsaicin- and peripheral ischemia-induced mechanical allodynia and thermal hyperalgesia. Anesth Analg. 2012;114(1):215-23.
Moon, J. Y., Song, S., Yoon, S. Y., Roh, D. H., Kang, S. Y., Park, J. H., Beitz, A. J., & Lee, J. H. (2012). The differential effect of intrathecal Nav1.8 blockers on the induction and maintenance of capsaicin- and peripheral ischemia-induced mechanical allodynia and thermal hyperalgesia. Anesthesia and Analgesia, 114(1), 215-23. https://doi.org/10.1213/ANE.0b013e318238002e
Moon JY, et al. The Differential Effect of Intrathecal Nav1.8 Blockers On the Induction and Maintenance of Capsaicin- and Peripheral Ischemia-induced Mechanical Allodynia and Thermal Hyperalgesia. Anesth Analg. 2012;114(1):215-23. PubMed PMID: 22127815.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The differential effect of intrathecal Nav1.8 blockers on the induction and maintenance of capsaicin- and peripheral ischemia-induced mechanical allodynia and thermal hyperalgesia. AU - Moon,Ji-Young, AU - Song,Sunok, AU - Yoon,Seo-Yeon, AU - Roh,Dae-Hyun, AU - Kang,Suk-Yun, AU - Park,Ji-Ho, AU - Beitz,Alvin J, AU - Lee,Jang-Hern, Y1 - 2011/11/29/ PY - 2011/12/1/entrez PY - 2011/12/1/pubmed PY - 2012/7/17/medline SP - 215 EP - 23 JF - Anesthesia and analgesia JO - Anesth Analg VL - 114 IS - 1 N2 - BACKGROUND: It has been reported that the selective blockade of Nav1.8 sodium channels could be a possible target for the development of analgesics without unwanted side effects. However, the precise role of spinal Nav1.8 in the induction and maintenance of persistent pain, e.g., mechanical allodynia (MA) and thermal hyperalgesia (TH), is not clear. We designed this study to investigate whether spinal Nav1.8 contributes to capsaicin-induced and peripheral ischemia-induced MA and TH. METHODS: The Nav1.8 blockers, A-803467 or ambroxol, were injected intrathecally either before or after intraplantar capsaicin injection. To evaluate capsaicin-induced neuronal activation in the spinal cord, we quantified the number of Fos-immunoreactive cells in the dorsal horn. In the thrombus-induced ischemic pain model, we determined the differential effect of A-803467 on the induction phase or maintenance phase of MA. RESULTS: Intrathecal injection of A-803467 (10, 30, 100 nmol) or ambroxol (241, 724, 2410 nmol) before intraplantar injection of capsaicin dose dependently prevented the induction of both MA and TH. However, posttreatment with A-803467 (100 nmol) and ambroxol (2410 nmol) did not reduce the MA that had already developed, but did significantly suppress capsaicin-induced TH. Moreover, the capsaicin-induced increase of spinal Fos-immunoreactive cells was significantly diminished by pretreatment, but not posttreatment with Nav1.8 blockers. In thrombus-induced ischemic pain rats, repetitive treatments of A-803467 during the induction period also prevented the development of MA, whereas A-803467 treatments during the maintenance period were ineffective in preventing or reducing MA. CONCLUSIONS: These results demonstrate that spinal activation of Nav1.8 mediates the early induction of MA, but not the maintenance of MA. However, both the induction and maintenance of TH are modulated by the intrathecal injection of Nav1.8 blockers. These findings suggest that early treatment with a Nav1.8 blocker can be an important factor in the clinical management of chronic MA associated with inflammatory and ischemic pain. SN - 1526-7598 UR - https://www.unboundmedicine.com/medline/citation/22127815/The_differential_effect_of_intrathecal_Nav1_8_blockers_on_the_induction_and_maintenance_of_capsaicin__and_peripheral_ischemia_induced_mechanical_allodynia_and_thermal_hyperalgesia_ L2 - https://doi.org/10.1213/ANE.0b013e318238002e DB - PRIME DP - Unbound Medicine ER -