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.