TRANSLATIONAL PHYSIOLOGY Opioid-induced hypernociception is associated with hyperexcitability and altered tetrodotoxin-resistant Na channel function of dorsal root ganglia

Ross GR, Gade AR, Dewey WL, Akbarali HI. Opioid-induced hypernociception is associated with hyperexcitability and altered tetrodotoxin-resistant Na channel function of dorsal root ganglia. Am J Physiol Cell Physiol 302: C1152–C1161, 2012. First published December 21, 2011; doi:10.1152/ajpcell.00171.2011.—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 tetrodotoxinresistant (TTX-R) Na and transient receptor potential vanilloid 1 (TRPV1) channels of dorsal root ganglia neurons (DRG) (L5–S1) 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 (V1/2) 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 V1/2 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.