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.

Inhibitory Effects of Mas-Related Gene C Receptor on Chronic Morphine-Induced Spinal Glial Activation in Rats

“…We demonstrated that chronic exposure to morphine increased the expression of TLR 4 and fractalkine in DRG in vivo and/or ex vivo. These results can be interpreted as the involvement of TLR 4 and fractalkine in morphine tolerance, since the increase in TLR 4 (Due et al, 2012(Due et al, , 2014 and fractalkine (Souza et al, 2013) signaling can induce hyperexcitability of DRG neurons. On the other hand, treatment with BAM8-22 abolished increases in TLR 4 and fractalkine induced by chronic morphine in and/or ex vivo.…”

“…TLR 4 is present in sensory neurons, but not in non-neuronal cells, in the DRG (Due et al, 2012). Activation of TLR 4 induces hyperexcitability of DRG neurons by increasing sodium current (Due et al, 2012(Due et al, , 2014. Fractalkine, also named CX3CL1, is a chemokine and is only expressed in neurons, not in glial cells, in DRG (Verge et al, 2004;Milligan et al, 2008).…”

Small-molecule Ca V α 1 ⋅Ca V β antagonist suppresses neuronal voltage-gated calcium-channel trafficking

“…5B) (53). TNI induces prolonged chronic behavioral hypersensitivity to mechanical stimuli which lasts for several months and is generally insensitive to opioids such as morphine (53,54). Before exposure to the compound, all injured animals exhibited pronounced mechanical allodynia (33.1 ± 5.9 mN; n = 8-10) in response to von Frey hair stimulation of the injured hind paw, compared with presurgery levels, which averaged 68.7 ± 3.7 mN (n = 8-10) (Fig.…”

Impact of Opioid and Nonopioid Drugs on Postsurgical Pain Management in the Rat

“…Although neither of these modes of action can be completely ruled out, the clinical OIH mechanism may also depend on opioid-induced activation of neuronal Toll-like receptor 4 (TLR4) [ 42 ]. Recent preclinical evidence suggests that opioid activation of TLR4 present on nociceptive primary sensory neurons cells serves to increase the voltage gated sodium channel (VGSC-NaV1.7; SCN9A in humans) current density which contributes directly to the diminished efficacy of opioids in chronic pain management [ 36 , 43 ].…”