J Korean Med Sci.  2013 Feb;28(2):300-307. 10.3346/jkms.2013.28.2.300.

Intrathecal Lamotrigine Attenuates Antinociceptive Morphine Tolerance and Suppresses Spinal Glial Cell Activation in Morphine-Tolerant Rats

• Jun IG
• Kim SH
• Yoon YI
• Park JY

• KMID: 1429208
• DOI: http://doi.org/10.3346/jkms.2013.28.2.300

Abstract

Glial cells play a critical role in morphine tolerance, resulting from repeated administration of morphine. Both the development and the expression of tolerance are suppressed by the analgesic lamotrigine. This study investigated the relationship between the ability of lamotrigine to maintain the antinociceptive effect of morphine during tolerance development and glial cell activation in the spinal cord. In a rat model, morphine (15 microg) was intrathecally injected once daily for 7 days to induce morphine tolerance. Lamotrigine (200 microg) was co-administered with morphine either for 7 days or the first or last 3 days of this 7 day period. Thermal nociception was measured. OX-42 and GFAP immunoreactivity, indicating spinal microglial and astrocytic activation were evaluated on day 8. Tolerance developed after 7 days of intrathecal morphine administration; however, this was completely blocked and reversed by co-administration of lamotrigine. When lamotrigine was coinjected with morphine on days 5-7, the morphine effect was partially restored. Glial cell activation increased with the development of morphine tolerance but was clearly inhibited in the presence of lamotrigine. These results suggest that, in association with the suppression of spinal glial cell activity, intrathecally coadministered lamotrigine attenuates antinociceptive tolerance to morphine.

Keyword

Astrocyte; Intrathecal; Lamotrigine; Microglia; Morphine; Tolerance

MeSH Terms

Analgesics/*pharmacology
Animals
Antigens, CD11b/metabolism
Astrocytes/cytology
Drug Tolerance
Immunohistochemistry
Male
Microglia/cytology
Morphine/*pharmacology
Nerve Tissue Proteins/metabolism
Neuroglia/cytology/*metabolism
Rats
Rats, Sprague-Dawley
Spinal Cord/*cytology
Triazines/*pharmacology
Analgesics
Antigens, CD11b
Nerve Tissue Proteins
Triazines
Morphine

Figure

• 

  Fig. 1 The acute responses of thermal nociception (mean ± SEM) to intrathecal saline, morphine, lamotrigine, and morphine plus lamotrigine. All doses of morphine and lamotrigine are 5 µg and 200 µg, respectively. *P < 0.05 vs control group; †P < 0.05 vs morphine group; ‡P < 0.05 vs lamotrigine group. MPE, maximum possible effect.

• 

  Fig. 2 The chronic responses of thermal nociception (mean ± SEM) to intrathecal saline, morphine, lamotrigine, and morphine plus lamotrigine (lamotrigine given on days 1-7, days 5-7, or days 1-3). All doses of morphine and lamotrigine are 15 µg and 200 µg, respectively. *P < 0.05 vs control group; †P < 0.05 vs M1-7 group. Control: intrathecal injection of saline (10 µL) once daily for 7 days. M1-7: intrathecal injection of morphine (15 µg) once daily for 7 days. L1-7: intrathecal coinjection of morphine (15 µg) and lamotrigine (200 µg) once daily for 7 days. L5-7: intrathecal injection of morphine (15 µg) once daily for 4 days, followed by intrathecal coinjection of morphine (15 µg) and lamotrigine (200 µg) on days 5-7. L1-3: intrathecal coinjection of morphine (15 µg) and lamotrigine (200 µg) once daily for 3 days, followed by daily morphine alone on days 4-7.

• 

  Fig. 3 Spinal immunoreactivity to OX-42 under 200 × magnification after a 7 day treatment with intrathecal saline, morphine, and lamotrigine, and the combinations thereof. The number of OX-42-positive cells increased with the development of morphine tolerance but was clearly inhibited by the co-administration of 200 µg of lamotrigine. There were significantly fewer OX-42-positive cells in rats co-administered with 200 µg of lamotrigine during the first or last 3 days than in the morphine alone group. *P < 0.05 vs control group; †P < 0.05 vs M1-7 group. Control: intrathecal injection of saline (10 µL) once daily for 7 days. M1-7: intrathecal injection of morphine (15 µg) once daily for 7 days. L1-7: intrathecal coinjection of morphine (15 µg) and lamotrigine (200 µg) once daily for 7 days. L1-3: intrathecal coinjection of morphine (15 µg) and lamotrigine (200 µg) once daily for 3 days, followed by daily morphine alone on days 4-7. L5-7: intrathecal injection of morphine (15 µg) once daily for 4 days, followed by intrathecal coinjection of morphine (15 µg) and lamotrigine (200 µg) on days 5-7.

• 

  Fig. 4 Spinal immunoreactivity to glial fibrillary acidic protein (GFAP), as observed under 200 × magnification, after a 7 day treatment with intrathecal saline, morphine, and lamotrigine, and combinations thereof. The development of morphine tolerance was accompanied by an increase in the number of GFAP-positive cells, which was clearly inhibited by the coadministration of 200 µg of lamotrigine. There were significantly fewer GFAP-positive cells in the groups of rats co-administered 200 µg of lamotrigine during the first or last 3 days than in the morphine alone group. *P < 0.05 vs control group; †P < 0.05 vs M1-7 group. Control: intrathecal injection of saline (10 µL) once daily for 7 days. M1-7: intrathecal injection of morphine (15 µg) once daily for 7 days. L1-7: intrathecal coinjection of morphine (15 µg) and lamotrigine (200 µg) once daily for 7 days. L1-3: intrathecal coinjection of morphine (15 µg) and lamotrigine (200 µg) once daily for 3 days, followed by daily morphine alone on days 4-7. L5-7: intrathecal injection of morphine (15 µg) once daily for 4 days, followed by intrathecal coinjection of morphine (15 µg) and lamotrigine (200 µg) on days 5-7.

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