title: Opioid-induced hypernociception is associated with hyperexcitability and altered tetrodotoxin-resistant Na+ channel function of dorsal root ganglia.
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.
authors.affiliation: Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, 23298-0524, USA.
authors.forename: Gracious R
authors.initials: GR
authors.lastname: Ross
authors.forename: Aravind R
authors.initials: AR
authors.lastname: Gade
authors.forename: William L
authors.initials: WL
authors.lastname: Dewey
authors.forename: Hamid I
authors.initials: HI
authors.lastname: Akbarali
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000701:Analgesics, Opioid / Q000633:toxicity*; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009020:Morphine / Q000633:toxicity; D059225:Nociception / Q000187:drug effects* / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology*
chemical_list: D000701:Analgesics, Opioid; D012333:RNA, Messenger; D015222:Sodium Channels; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D013779:Tetrodotoxin; D009020:Morphine; D012964:Sodium; D002211:Capsaicin