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

Abstract

Ross GR, Gade AR, Dewey WL, Akbarali HI. Opioid-induced hypernociception is associated with hyperexcitability and altered tetrodotoxin-resistant Na ϩ channel function of dorsal root ganglia. Am J Physiol Cell Physiol 302: C1152-C1161, 2012. First published December 21, 2011; doi:10.1152/ajpcell.00171.2011Opiates 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 ϩ 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 Ͻ 0.01) lower (38 Ϯ 7 vs. 100 Ϯ 15 pA) while the number of APs at 2ϫ rheobase was higher (4.4 Ϯ 0.8 vs. 2 Ϯ 0.5) than placebo (n ϭ 13-20). The potential of half-maximum activation (V1/2) of TTX-R Na ϩ currents was shifted to more hyperpolarized potential in the chronic morphine group (Ϫ37 Ϯ 1 mV) vs. placebo (Ϫ28 Ϯ 1 mV) without altering the V1/2 of inactivation (Ϫ41 Ϯ 1 vs. Ϫ33 Ϯ 1 mV) (n ϭ 8 -11). Recovery rate from inactivation of TTX-R Na ϩ channels or the mRNA level of any Na ϩ channel subtypes did not change after chronic morphine. Also, chronic morphine significantly (P Ͻ 0.05) enhanced the magnitude of TRPV1 currents (Ϫ64 Ϯ 11 pA/pF) vs. placebo (Ϫ18 Ϯ 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 ϩ currents. Enhanced TRPV1 currents may have a complementary effect, with TTX-R Na ϩ 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 ϩ and TRPV1 channels of sensory neurons.morphine hyperalgesia pain transient receptor potential vanilloid 1 channels CLINICAL MANAGEMENT OF PAIN proceeds in a stepwise fashion, based on pain intensity and duration as depicted in the analgesic ladder generated by the World Health Organization (60). Typically, narcotic opiate regimens, including morphine, are used to treat moderate to severe pain. Paradoxically, patients undergoing chronic opiate therapy have reported abnormal pain, even in regions away from the initial site of pain (4,26,27,49). In addition to tolerance development to the analgesic effects of opiates being a major impediment to pain therapy, chronic opiate-induced hypernociception has become a critical problem. This phenomenon of opiate-induced hypernociception is also demonstrated in several experimental animal models such as thermal and tactile nociception in mice (56) as well as in a rat model of narcotic bowel syndro...

Differential tolerance to morphine antinociception in assays of pain-stimulated vs. pain-depressed behavior in rats

“…This agrees with previous reports of “opioid-induced hyperalgesia” following regimens of opioid exposure in assays of acid-stimulated stretching in mice (Li et al, 2014) and in other preclinical assays of pain-stimulated behavior (Dong et al, 2006; Ross et al, 2012; Wei and Wei, 2012). Hyperalgesia after repeated treatment with morphine or other mu opioid agonists has also been reported in humans (De Conno et al, 1991; Chu et al, 2008; Lee et al, 2011).…”

GluN2B N-methyl-D-aspartate receptor and excitatory amino acid transporter 3 are upregulated in primary sensory neurons after 7 days of morphine administration in rats

“…In DRGs TLR4 is expressed by neurons rather than by glial cells [12; 74]. Binding of morphine or possibly its metabolite morphine-3-glucuronide (M3G) to TLR4 activates a cascade of events leading to greater neuronal excitability through an increased activity of sodium channels [12; 58; 60], transient receptor potential channels [15; 60; 61], and inflammatory mediators [12; 81]. Some of these events are likely contributors to the altered function of primary sensory neurons observed here.…”

“…The pump delivered the solution at a constant rate of 10 μl/h and lasted for 1 week. Continuous morphine administration for 7 days was previously shown to reliably induce OIH [60; 75]. Before implantation, the pumps were weighed.…”

“…While much of the attention has focused on the involvement of the central nervous system (CNS) [78; 86], there is growing evidence that the peripheral nervous system contributes to OIH, because of documented increased firing of primary nociceptive neurons or their fibers after morphine administration [23; 31; 60; 76]. After morphine administration primary afferent terminals in the spinal cord display increased activity, greater release of glutamate, and larger N-methyl-D-aspartate receptor (NMDAR) mediated responses [90].…”

“…After morphine administration primary afferent terminals in the spinal cord display increased activity, greater release of glutamate, and larger N-methyl-D-aspartate receptor (NMDAR) mediated responses [90]. Finally, dissociated small diameter dorsal root ganglion (DRG) neurons pre-exposed to morphine, in vivo or in vitro , exhibit an increased excitability [60; 76]. …”