KCNQ channels in nociceptive cold-sensing trigeminal ganglion neurons as therapeutic targets for treating orofacial cold hyperalgesia.

BACKGROUND: Hyperexcitability of nociceptive afferent fibers is an underlying mechanism of neuropathic pain and ion channels involved in neuronal excitability are potentially therapeutic targets. KCNQ channels, a subfamily of voltage-gated K(+) channels mediating M-currents, play a key role in neuronal excitability. It is unknown whether KCNQ channels are involved in the excitability of nociceptive cold-sensing trigeminal afferent fibers and if so, whether they are therapeutic targets for orofacial cold hyperalgesia, an intractable trigeminal neuropathic pain. METHODS: Patch-clamp recording technique was used to study M-currents and neuronal excitability of cold-sensing trigeminal ganglion neurons. Orofacial operant behavioral assessment was performed in animals with trigeminal neuropathic pain induced by oxaliplatin or by infraorbital nerve chronic constrictive injury. RESULTS: We showed that KCNQ channels were expressed on and mediated M-currents in rat nociceptive cold-sensing trigeminal ganglion (TG) neurons. The channels were involved in setting both resting membrane potentials and rheobase for firing action potentials in these cold-sensing TG neurons. Inhibition of KCNQ channels by linopirdine significantly decreased resting membrane potentials and the rheobase of these TG neurons. Linopirdine directly induced orofacial cold hyperalgesia when the KCNQ inhibitor was subcutaneously injected into rat orofacial regions. On the other hand, retigabine, a KCNQ channel potentiator, suppressed the excitability of nociceptive cold-sensing TG neurons. We further determined whether KCNQ channel could be a therapeutic target for orofacial cold hyperalgesia. Orofacial cold hyperalgesia was induced in rats either by the administration of oxaliplatin or by infraorbital nerve chronic constrictive injury. Using the orofacial operant test, we showed that retigabine dose-dependently alleviated orofacial cold hyperalgesia in both animal models. CONCLUSION: Taken together, these findings indicate that KCNQ channel plays a significant role in controlling cold sensitivity and is a therapeutic target for alleviating trigeminal neuropathic pain that manifests orofacial cold hyperalgesia.

Operant behavioral responses to orofacial cold stimuli in rats with chronic constrictive trigeminal nerve injury: effects of menthol and capsazepine.

Both spinal and trigeminal somatosensory systems use the TRPM8 channel as a principal transducer for detecting cold stimuli. It is currently unclear whether this cold transducer may play a role in trigeminal neuropathic pain manifesting cold allodynia and hyperalgesia. In the present study, trigeminal neuropathy was induced by chronic constrictive nerve injury of the infraorbital nerve (ION-CCI). Behavioral responses to cold stimuli in orofacial regions were assessed by the newly developed orofacial operant test in the ION-CCI rats. We tested menthol and capsazepine, two compounds that can activate and inhibit TRPM8 respectively, on orofacial operant responses to cold stimuli in ION-CCI rats. Testing animals performed operant tasks by voluntarily contacting their orofacial regions to a cold stimulation module in order to access sweetened milk as a reward, and contact time and number of the operant behaviors were automatically recorded. Total contact time was significantly reduced at the cooling temperatures of 17°C and 12°C in ION-CCI group in comparison with sham group, indicating the presence of cold allodynia and hyperalgesia in ION-CCI rats. When menthol was administered to ION-CCI rats, total contact time was further reduced and total contact number increased at the cooling temperatures. In contrast, after administration of capsazepine to ION-CCI rats, total contact time was significantly increased at the cooling temperatures. The behavioral outcomes support the idea that TRPM8 plays a role in cold allodynia and hyperalgesia following chronic trigeminal nerve injury.

Assessment of chronic trigeminal neuropathic pain by the orofacial operant test in rats.

Classical behavioral tests in animal models of trigeminal neuropathic pain measure reflexive responses that are not necessarily measures of pain. To overcome the problem, we created a chronic constrictive nerve injury (CCI) rat model of pain by ligation of the infraorbital nerve (ION), and applied the orofacial operant test to assess behavioral responses to mechanical and cold stimulation in these rats. Animals were trained to voluntarily contact their facial region to a mechanical or a cold stimulation module in order to access sweetened milk as a positive reward. ION-CCI rats displayed aversive behaviors to innocuous mechanical stimuli, as indicated by a significant decrease in both contact time and the numbers of long contact events in comparison with sham group. For cold stimulation, ION-CCI rats displayed aversive behaviors to both innocuous (17 °C) and noxious cold temperatures (12 °C and 5 °C), as indicated by a significant decrease in both contact time and the numbers of long contact events at the cooling temperatures. The decreases of the contact time and numbers in ION-CCI rats were partially abolished by morphine. Our orofacial operant test demonstrates mechanical allodynia, cold allodynia, and hyperalgesia in rats with chronic trigeminal nerve injury. The neuropathic pain in ION-CCI rats was partially alleviated by morphine. Thus, orofacial operant test provides a desirable behavioral assessment method for preclinical studies of chronic trigeminal neuropathic pain.