We were intrigued by the recent study in which two NSAIDs, the class of drugs which are the first line clinical treatment for TMD pain, were shown to suppress epileptic activities by activation of neuronal voltage-gated KCNQ/Kv7 channels . This observation led us to hypothesize that the anticonvulsant retigabine that specifically opens KCNQ/Kv7 channels might be beneficial for TMD pain. In this study for the first time, we have shown that central activation of neuronal KCNQ/Kv7 potassium channels by retigabine can attenuate allodynia associated with temporomandibular joint inflammation in rats. Our findings have several implications: first, they serve as an in vivo validation that neuronal KCNQ/Kv7 potassium channels are a target for TMJ pain; second, the positive modulation of neuronal KCNQ/Kv7 potassium channels that suppress excessive excitability can be therapeutically beneficial to TMDs; third, the anticonvulsant retigabine which is effective in clinical trials for reduction in seizures may also prove to be useful in pharmacological intervention in TMDs; finally, central hyperexcitability is involved in the mechanism of inflammatory TMJ pain.
TMD pain is considered to be a disorder characterized by central hyperexcitability and sensitization, and this is further supported by the fact that central-acting pharmacological agents including the anticonvulsant gabapentin show clinical efficacy for analgesia and anti-hyperalgesia in treatment of TMDs [7, 8]. Neuronal hyperexcitability is a common underlying mechanism of neurological disorders such as epilepsy and chronic pain including TMDs. These disorders are currently managed by drugs that are dampen neuronal hyperexcitability through voltage-gated sodium channel inhibition, modulation of voltage-gated calcium channels and their auxiliary subunits, and inhibitory GABAergic neurotransmission . Although the cause of excessive neuronal activity varies, an increase in voltage-gated K+ channel conductance can suppress the hyerexcitability, thus providing a therapeutic potential for chronic pain. The voltage-gated potassium channels play a common role in repolarizing membrane potential of neurons during action potential firing. Typical neuronal firing is characterized by a specific voltage threshold for action potential, and the opening of potassium channels below the threshold (or subthreshold) will lead to the inhibition of initiation and propagation of action potential.
Head withdrawal is a response to nociceptive stimuli applied to the facial skin, and head withdrawal threshold is regulated by excitability of TRG neurons innervating the TMJ . It has been shown that voltage-gated transient potassium (Kv) current regulates the excitability of TRG neurons, and the Kv channel density is lower in inflamed TMJ, leading to increased excitability of TRG neurons [25, 33]. In terms of action mechanism of retigabine, there is a lack of literature report as to whether KCNQ/M-current is expressed in TRG neurons, and our data can not rule out retigabine partially working on peripheral TRG neurons for activation of Kv current.
The existence of a low-threshold, depolarization activated potassium current was described in 1980 and is referred to as the "M-current" because it was inhibited by the cholinergic agonist muscacine [34, 35]. The M-current is active in the voltage range for action potential initiation and is therefore of particular importance in regulating the dynamics of the neuronal firing of nociceptive neurons and excitability of C-type nerve fibers [14, 15]. The M-current turns on slowly following membrane depolarization and does not inactivate with sustained depolarization. The molecular identity that underlies the M-current was discovered as a result of identification of mutations in human potassium channel subunits referred to as KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) from idiopathic generalized epilepsy patients [36, 37]. It was demonstrated that the M-current channel is formed by KCNQ2 and KCNQ3 subunits as heteromultimers as well as homomultimers . M-current can also possibly be generated by heteromultimers with other KCNQ subunits such as KCNQ5 . The expression of KCNQ subunits has also been confirmed in the CNS and DRG sensory neurons [10, 39, 40], suggesting the role the channels play in regulating neuronal excitability.
There are no previously published studies in the literature evaluating the analgesic effect of retigabine on TMJ pain. Pharmacological treatment of TMDs remains a clinical challenge because of diverse etiologic factors that contribute to the severity of TMDs pain. Without a clear rationale based on mechanism for selection of drugs, a wide-spectrum of available drugs such as NSAIDs, antidepressants, benzodiazepines, muscle relaxants, corticosteroids, anticonvulsants and opioids etc, has been used to achieve desired therapeutic end points for TMDs. Accumulating clinical evidence shows that patients with TMDs have generalized central hypersensitivity, suggesting that anticonvulsant drugs may have therapeutic potential [1, 5, 8]. Retigabine is a promising new anticonvulsant that has been shown to have a broad-spectrum of activity in animal models of epileptic seizures with a recently described novel mechanism of action which involves specific activation of KCNQ2-5 (Kv7.2-7.5) channels [9, 41–43]. There are preliminary indications that in the rat the half-life and concentrations of retigabine are higher in the brain than in the plasma . Retigabine has also been shown to relieve hyperalgesia and allodynia in animal models of neuropathic pain [9, 10]. In previous studies of rotarod test that evaluates balancing and coordination for CNS side effect , a dose of 10 mg/kg retigabine was given to rats intraperitoneally to test its side effects of central nervous system. The administration of retigabine caused a short period of impaired motor performance, although the motor performance of all rats returned to baseline level 15 min after administration of the drug . In order to avoid performance impairment, we reduced the dose to 7.5 mg/kg, and no significant performance impairment was observed during the behavior test in our study. We also tested the effect of retigabine and XE991 on normal rats, and we did not observe any abnormal pain sensation or abnormality of food intake with these agents. This result indicates that that retigabine preferentially functions in hyperactive neurons, which is consistent with the observation that the effect of retigabine is profound in depolarized neurons and small in hyperpolarized axons [14, 15]. Taken these findings together, the pharmacological effect of retigabine on TMJ inflammation was specific, and was not due to any toxic effect .