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

Abstract

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 model. 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.Key words neuropathic pain; intrathecal; combination drug therapy; ketamine; pregabalin; mouse 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][11][12][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 cen...

Inhibition of DOR prevents remifentanil induced postoperative hyperalgesia through regulating the trafficking and function of spinal NMDA receptors in vivo and in vitro

“…Many studies indicate that low-dose NMDA receptor antagonist ketamine can prevent remifentanil-induced hyperalgesia, suggesting that NMDA receptors are related to the mechanism of OIH (Hang et al, 2011;Joly et al, 2005). However, the clinical application of ketamine to prevent hyperalgesia is limited because of side effects such as somnolence, dizziness and sedation (Lim et al, 2013). Furthermore, blockade of NMDA receptor function may affect the normal physiological functions.…”

A comparison of intrathecal magnesium and ketamine in attenuating remifentanil-induced hyperalgesia in rats

“…However, the clinical application of ketamine to prevent hyperalgesia is limited because of side effects such as somnolence, dizziness and sedation [27]. …”

“…ketamine intrathecally had no effect on postoperative analgesia [27]. Rota rod test revealed that motor dysfunction was found with the use of i.t.…”

“…Rota rod test revealed that motor dysfunction was found with the use of i.t. ketamine at doses above 10 μg [27]. So the dose of 10 μg ketamine was selected for use in the current trial.…”

Clonidine Reduces Nociceptive Responses in Mouse Orofacial Formalin Model: Potentiation by Sigma-1 Receptor Antagonist BD1047 without Impaired Motor Coordination

“…25) We have also used the rota-rod test for mice to examine the potential sedative effects of clonidine. 26) The Roto-rod apparatus (model# DJ-4009; Dae-Jong Engineering & Clean Technology, Seoul, Korea) consisted of a rotating horizontal bar (diameter=6 cm), which was subdivided into 4 compartments by rotating plates.…”