Carbamazepine potentiates the effectiveness of morphine in a rodent model of neuropathic pain

Michael R. Due, Xiao Fang Yang, Yohance M. Allette, Aaron L. Randolph, Matthew S. Ripsch, Sarah M. Wilson, Erik T. Dustrude, Rajesh Khanna, Fletcher White

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Approximately 60% of morphine is glucuronidated to morphine-3-glucuronide (M3G) which may aggravate preexisting pain conditions. Accumulating evidence indicates that M3G signaling through neuronal Toll-like receptor 4 (TLR4) may be central to this proalgesic signaling event. These events are known to include elevated neuronal excitability, increased voltage-gated sodium (NaV) current, tactile allodynia and decreased opioid analgesic efficacy. Using an in vitro ratiometric-based calcium influx analysis of acutely dissociated small and medium-diameter neurons derived from lumbar dorsal root ganglion (DRG), we observed that M3G-sensitive neurons responded to lipopolysaccharide (LPS) and over 35% of these M3G/LPS-responsive cells exhibited sensitivity to capsaicin. In addition, M3G-exposed sensory neurons significantly increased excitatory activity and potentiated NaV current as measured by current and voltage clamp, when compared to baseline level measurements. The M3G-dependent excitability and potentiation of NaV current in these sensory neurons could be reversed by the addition of carbamazepine (CBZ), a known inhibitor of several NaV currents. We then compared the efficacy between CBZ and morphine as independent agents, to the combined treatment of both drugs simultaneously, in the tibial nerve injury (TNI) model of neuropathic pain. The potent anti-nociceptive effects of morphine (5 mg/kg, i.p.) were observed in TNI rodents at post-injury day (PID) 7-14 and absent at PID21-28, while administration of CBZ (10 mg/kg, i.p.) alone failed to produce anti-nociceptive effects at any time following TNI (PID 7-28). In contrast to either drug alone at PID28, the combination of morphine and CBZ completely attenuated tactile hyperalgesia in the rodent TNI model. The basis for the potentiation of morphine in combination with CBZ may be due to the effects of a latent upregulation of NaV1.7 in the DRG following TNI. Taken together, our observations demonstrate a potential therapeutic use of morphine and CBZ as a combinational treatment for neuropathic pain.

Original languageEnglish (US)
Article numbere107399
JournalPLoS One
Volume9
Issue number9
DOIs
StatePublished - Sep 15 2014

Fingerprint

morphine
Carbamazepine
Neuralgia
Morphine
Tibial Nerve
pain
Rodentia
rodents
Neurons
Wounds and Injuries
nerve tissue
Hyperalgesia
Spinal Ganglia
Sensory Receptor Cells
Lipopolysaccharides
Level measurement
Toll-Like Receptor 4
analgesic effect
sensory neurons
Capsaicin

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Due, M. R., Yang, X. F., Allette, Y. M., Randolph, A. L., Ripsch, M. S., Wilson, S. M., ... White, F. (2014). Carbamazepine potentiates the effectiveness of morphine in a rodent model of neuropathic pain. PLoS One, 9(9), [e107399]. https://doi.org/10.1371/journal.pone.0107399

Carbamazepine potentiates the effectiveness of morphine in a rodent model of neuropathic pain. / Due, Michael R.; Yang, Xiao Fang; Allette, Yohance M.; Randolph, Aaron L.; Ripsch, Matthew S.; Wilson, Sarah M.; Dustrude, Erik T.; Khanna, Rajesh; White, Fletcher.

In: PLoS One, Vol. 9, No. 9, e107399, 15.09.2014.

Research output: Contribution to journalArticle

Due, MR, Yang, XF, Allette, YM, Randolph, AL, Ripsch, MS, Wilson, SM, Dustrude, ET, Khanna, R & White, F 2014, 'Carbamazepine potentiates the effectiveness of morphine in a rodent model of neuropathic pain', PLoS One, vol. 9, no. 9, e107399. https://doi.org/10.1371/journal.pone.0107399
Due MR, Yang XF, Allette YM, Randolph AL, Ripsch MS, Wilson SM et al. Carbamazepine potentiates the effectiveness of morphine in a rodent model of neuropathic pain. PLoS One. 2014 Sep 15;9(9). e107399. https://doi.org/10.1371/journal.pone.0107399
Due, Michael R. ; Yang, Xiao Fang ; Allette, Yohance M. ; Randolph, Aaron L. ; Ripsch, Matthew S. ; Wilson, Sarah M. ; Dustrude, Erik T. ; Khanna, Rajesh ; White, Fletcher. / Carbamazepine potentiates the effectiveness of morphine in a rodent model of neuropathic pain. In: PLoS One. 2014 ; Vol. 9, No. 9.
@article{b2fe89de1c58436e98757f01275b75bb,
title = "Carbamazepine potentiates the effectiveness of morphine in a rodent model of neuropathic pain",
abstract = "Approximately 60{\%} of morphine is glucuronidated to morphine-3-glucuronide (M3G) which may aggravate preexisting pain conditions. Accumulating evidence indicates that M3G signaling through neuronal Toll-like receptor 4 (TLR4) may be central to this proalgesic signaling event. These events are known to include elevated neuronal excitability, increased voltage-gated sodium (NaV) current, tactile allodynia and decreased opioid analgesic efficacy. Using an in vitro ratiometric-based calcium influx analysis of acutely dissociated small and medium-diameter neurons derived from lumbar dorsal root ganglion (DRG), we observed that M3G-sensitive neurons responded to lipopolysaccharide (LPS) and over 35{\%} of these M3G/LPS-responsive cells exhibited sensitivity to capsaicin. In addition, M3G-exposed sensory neurons significantly increased excitatory activity and potentiated NaV current as measured by current and voltage clamp, when compared to baseline level measurements. The M3G-dependent excitability and potentiation of NaV current in these sensory neurons could be reversed by the addition of carbamazepine (CBZ), a known inhibitor of several NaV currents. We then compared the efficacy between CBZ and morphine as independent agents, to the combined treatment of both drugs simultaneously, in the tibial nerve injury (TNI) model of neuropathic pain. The potent anti-nociceptive effects of morphine (5 mg/kg, i.p.) were observed in TNI rodents at post-injury day (PID) 7-14 and absent at PID21-28, while administration of CBZ (10 mg/kg, i.p.) alone failed to produce anti-nociceptive effects at any time following TNI (PID 7-28). In contrast to either drug alone at PID28, the combination of morphine and CBZ completely attenuated tactile hyperalgesia in the rodent TNI model. The basis for the potentiation of morphine in combination with CBZ may be due to the effects of a latent upregulation of NaV1.7 in the DRG following TNI. Taken together, our observations demonstrate a potential therapeutic use of morphine and CBZ as a combinational treatment for neuropathic pain.",
author = "Due, {Michael R.} and Yang, {Xiao Fang} and Allette, {Yohance M.} and Randolph, {Aaron L.} and Ripsch, {Matthew S.} and Wilson, {Sarah M.} and Dustrude, {Erik T.} and Rajesh Khanna and Fletcher White",
year = "2014",
month = "9",
day = "15",
doi = "10.1371/journal.pone.0107399",
language = "English (US)",
volume = "9",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "9",

}

TY - JOUR

T1 - Carbamazepine potentiates the effectiveness of morphine in a rodent model of neuropathic pain

AU - Due, Michael R.

AU - Yang, Xiao Fang

AU - Allette, Yohance M.

AU - Randolph, Aaron L.

AU - Ripsch, Matthew S.

AU - Wilson, Sarah M.

AU - Dustrude, Erik T.

AU - Khanna, Rajesh

AU - White, Fletcher

PY - 2014/9/15

Y1 - 2014/9/15

N2 - Approximately 60% of morphine is glucuronidated to morphine-3-glucuronide (M3G) which may aggravate preexisting pain conditions. Accumulating evidence indicates that M3G signaling through neuronal Toll-like receptor 4 (TLR4) may be central to this proalgesic signaling event. These events are known to include elevated neuronal excitability, increased voltage-gated sodium (NaV) current, tactile allodynia and decreased opioid analgesic efficacy. Using an in vitro ratiometric-based calcium influx analysis of acutely dissociated small and medium-diameter neurons derived from lumbar dorsal root ganglion (DRG), we observed that M3G-sensitive neurons responded to lipopolysaccharide (LPS) and over 35% of these M3G/LPS-responsive cells exhibited sensitivity to capsaicin. In addition, M3G-exposed sensory neurons significantly increased excitatory activity and potentiated NaV current as measured by current and voltage clamp, when compared to baseline level measurements. The M3G-dependent excitability and potentiation of NaV current in these sensory neurons could be reversed by the addition of carbamazepine (CBZ), a known inhibitor of several NaV currents. We then compared the efficacy between CBZ and morphine as independent agents, to the combined treatment of both drugs simultaneously, in the tibial nerve injury (TNI) model of neuropathic pain. The potent anti-nociceptive effects of morphine (5 mg/kg, i.p.) were observed in TNI rodents at post-injury day (PID) 7-14 and absent at PID21-28, while administration of CBZ (10 mg/kg, i.p.) alone failed to produce anti-nociceptive effects at any time following TNI (PID 7-28). In contrast to either drug alone at PID28, the combination of morphine and CBZ completely attenuated tactile hyperalgesia in the rodent TNI model. The basis for the potentiation of morphine in combination with CBZ may be due to the effects of a latent upregulation of NaV1.7 in the DRG following TNI. Taken together, our observations demonstrate a potential therapeutic use of morphine and CBZ as a combinational treatment for neuropathic pain.

AB - Approximately 60% of morphine is glucuronidated to morphine-3-glucuronide (M3G) which may aggravate preexisting pain conditions. Accumulating evidence indicates that M3G signaling through neuronal Toll-like receptor 4 (TLR4) may be central to this proalgesic signaling event. These events are known to include elevated neuronal excitability, increased voltage-gated sodium (NaV) current, tactile allodynia and decreased opioid analgesic efficacy. Using an in vitro ratiometric-based calcium influx analysis of acutely dissociated small and medium-diameter neurons derived from lumbar dorsal root ganglion (DRG), we observed that M3G-sensitive neurons responded to lipopolysaccharide (LPS) and over 35% of these M3G/LPS-responsive cells exhibited sensitivity to capsaicin. In addition, M3G-exposed sensory neurons significantly increased excitatory activity and potentiated NaV current as measured by current and voltage clamp, when compared to baseline level measurements. The M3G-dependent excitability and potentiation of NaV current in these sensory neurons could be reversed by the addition of carbamazepine (CBZ), a known inhibitor of several NaV currents. We then compared the efficacy between CBZ and morphine as independent agents, to the combined treatment of both drugs simultaneously, in the tibial nerve injury (TNI) model of neuropathic pain. The potent anti-nociceptive effects of morphine (5 mg/kg, i.p.) were observed in TNI rodents at post-injury day (PID) 7-14 and absent at PID21-28, while administration of CBZ (10 mg/kg, i.p.) alone failed to produce anti-nociceptive effects at any time following TNI (PID 7-28). In contrast to either drug alone at PID28, the combination of morphine and CBZ completely attenuated tactile hyperalgesia in the rodent TNI model. The basis for the potentiation of morphine in combination with CBZ may be due to the effects of a latent upregulation of NaV1.7 in the DRG following TNI. Taken together, our observations demonstrate a potential therapeutic use of morphine and CBZ as a combinational treatment for neuropathic pain.

UR - http://www.scopus.com/inward/record.url?scp=84907260398&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907260398&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0107399

DO - 10.1371/journal.pone.0107399

M3 - Article

C2 - 25221944

AN - SCOPUS:84907260398

VL - 9

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 9

M1 - e107399

ER -