Faculty Collaboration Database

Opioid-induced hypernociception is associated with hyperexcitability and altered tetrodotoxin-resistant Na+ channel function of dorsal root ganglia. Am J Physiol Cell Physiol 2012 Apr 15;302(8):C1152-61

Date

12/23/2011

Pubmed ID

22189556

Pubmed Central ID

PMC3330728

DOI

10.1152/ajpcell.00171.2011

Scopus ID

2-s2.0-84859783544 (requires institutional sign-in at Scopus site)   22 Citations

Abstract

Opiates are potent analgesics for moderate to severe pain. Paradoxically, patients under chronic opiates have reported hypernociception, the mechanisms of which are unknown. Using standard patch-clamp technique, we examined the excitability, biophysical properties of tetrodotoxin-resistant (TTX-R) Na(+) and transient receptor potential vanilloid 1 (TRPV1) channels of dorsal root ganglia neurons (DRG) (L(5)-S(1)) from mice pelleted with morphine (75 mg) or placebo (7 days). Hypernociception was confirmed by acetic acid-writhing test following 7-day morphine. Chronic morphine enhanced the neuronal excitability, since the rheobase for action potential (AP) firing was significantly (P < 0.01) lower (38 ± 7 vs. 100 ± 15 pA) while the number of APs at 2× rheobase was higher (4.4 ± 0.8 vs. 2 ± 0.5) than placebo (n = 13-20). The potential of half-maximum activation (V(1/2)) of TTX-R Na(+) currents was shifted to more hyperpolarized potential in the chronic morphine group (-37 ± 1 mV) vs. placebo (-28 ± 1 mV) without altering the V(1/2) of inactivation (-41 ± 1 vs. -33 ± 1 mV) (n = 8-11). Recovery rate from inactivation of TTX-R Na(+) channels or the mRNA level of any Na(+) channel subtypes did not change after chronic morphine. Also, chronic morphine significantly (P < 0.05) enhanced the magnitude of TRPV1 currents (-64 ± 11 pA/pF) vs. placebo (-18 ± 6 pA/pF). The increased excitability of sensory neurons by chronic morphine may be due to the shift in the voltage threshold of activation of TTX-R Na(+) currents. Enhanced TRPV1 currents may have a complementary effect, with TTX-R Na(+) currents on opiate-induced hyperexcitability of sensory neurons causing hypernociception. In conclusion, chronic morphine-induced hypernociception is associated with hyperexcitability and functional remodeling of TTX-R Na(+) and TRPV1 channels of sensory neurons.

Author List

Ross GR, Gade AR, Dewey WL, Akbarali HI

Author

Gracious R. Ross Research Scientist II in the Cardiovascular Center department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Action Potentials
Analgesics, Opioid
Animals
Capsaicin
Ganglia, Spinal
Male
Membrane Potentials
Mice
Morphine
Nociception
RNA, Messenger
Sensory Receptor Cells
Sodium
Sodium Channels
TRPV Cation Channels
Tetrodotoxin