Intrathecal Ketamine and Pregabalin at Sub-effective Doses Synergistically Reduces Neuropathic Pain without Motor Dysfunction in Mice

Hyung Sun Lim, Jae-Min Kim, Jae-Gyun Choi, Young Kwon Ko, Yong Sup Shin, Beyong Hwa Jeon, Jin Bong Park, Jang-Hern Lee, Hyun-Woo Kim
2013 Biological and Pharmaceutical Bulletin  
Peripheral or central nerve injury often leads to neuropathic pain. Although ketamine and pregabalin are first line options for the treatment of neuropathic pain, their clinical application is limited due to side effects such as sedation, dizziness and somnolence. We designed this study to determine whether the intrathecal (i.t.) co-treatment with ketamine and pregabalin at sub-effective low doses would elicit a sufficient pain relief without producing side effect in a neuropathic pain mouse
more » ... el. At day 7 after chronic constriction injury (CCI) of sciatic nerve, dose dependent effects of i.t. ketamine (3, 10, 30, 100 µg) or i.t. pregabalin (10, 30, 100 µg) on mechanical allodynia and thermal hyperalgesia were measured. For combination treatment, 3 or 10 µg of ketamine and 30 µg of pregabalin were selected because these doses of drugs were not effective on neuropathic pain. Interestingly, combined i.t. treatment groups (ketamine 3 µg+pregabalin 30 µg and ketamine 10 µg+pregabalin 30 µg) produced strong analgesia on neuropathic pain although these doses of ketamine and pregabalin alone are not effective. Moreover, rota rod test revealed that normal motor function was not affected by combined treatment while i.t. ketamine at doses above 10 µg showed a significant motor dysfunction. Results of this study suggested that i.t. co-treatment with ketamine and pregabalin at sub-effect low doses may be a useful therapeutic method for the treatment of neuropathic pain patients. Peripheral or central nerve injury by a cancer, trauma, and/ or metabolic disease condition may evoke chronic neuropathic pain which is characterized by a presence of spontaneous pain (pain sensation without any stimulation), allodynia (pain sensation by a non-noxious stimulation), and hyperalgesia (enhanced pain by a noxious stimulation). 1-4) The development and maintenance of neuropathic pain have been known to be closely associated with a variety of pathophysiologic changes, including peripheral and central sensitization. 5, 6) At the periphery, up-regulation of α2δ subunit of voltagedependent calcium channel in the dorsal root ganglion correlates with the onset of tactile allodynia in spinal nerve-injured rats. 7) Recently marketed drugs, gabapentin and pregabalin are used as a first line option for the treatment of neuropathic pain and its pain relief effect is induced by a blockade of Ca 2+ influx of sensory neuron via binding with α2δ subunit of Ca 2+ channel. 8, 9) In addition, these treatments inhibit the release of excitatory neurotransmitters including glutamate, substance P and calcitonin gene-related peptide at a rodent spinal cord. 10-13) However, use of α2δ subunit Ca 2+ channel blockers has been limited since relatively higher dose is needed to produce a sufficient pain relief and several adverse effects such as dizziness and somnolence have been reported. 14, 15) The N-methyl-d-aspartate (NMDA) receptor is highly expressed in the central nervous system and directly involved in the excitatory neurotransmission. 16) NMDA receptor plays an important role in the development and maintenance of central sensitization, a state of long-lasting increase in synaptic transmission, and neuropathic pain. 17) Spinally administered NMDA receptor antagonist including memantine and AP-5 remarkably attenuates spinal nerve ligation-induced allodynia. However, no antinociceptive effect is seen when NMDA antagonists are treated into the supra-spinal site (i.e. intracerebroventricular injection), suggesting that spinal NMDA receptor may be a main target to treat neuropathic pain. 18) One of NMDA antagonists, ketamine has been used as an anesthetic or analgesic both in human and animal. However, serious side effects of NMDA antagonists have been reported including a motor impairment as well as sedation. In this regard, newer approach strategy using a NMDA blocker to treat neuropathic pain is required. We hypothesized that the combining treatment with ketamine and pregabalin at sub-effective doses would suppress synergistically nerve injury-induced neuropathic pain without producing side effect. To examine this hypothesis, chronic constriction injury (CCI) neuropathic pain mouse model was employed. Ketamine or pregabalin was intrathecally injected to determine their individual dose-dependent analgesic effect. Based on the result of dose-response curve, these two agents were intrathecally co-administrated at sub-effective low doses. In addition, side effect such as motor dysfunction was examined by a rota-rod test.
doi:10.1248/bpb.b12-00760 pmid:23302645 fatcat:z6iud25zzrdajbbnp6eufjhrsy