**9. M-type Potassium Channels**

M-type potassium channels are voltage-gated potassium channels (M for muscarine) encoded by *KCNQ* genes. *KCNQ* genes encode five Kv7 subunits (Kv7.1–7.5) [98]. Kv7.2, 7.3, 7.4, and 7.5 are expressed in the nervous system. The M-type potassium channel mainly features Kv7.2 and Kv7.3, although other subunits can also contribute to the formation of M channels in some locations.

M channels were first discovered in sympathetic neurons [99]. When muscarinic agonists activate the muscarinic acetylcholine receptors, sympathetic neurons become more responsive to the synaptic inputs and can become burst firing, rather than fire a single spike. This situation is due to the suppression of a unique channel, which led to the name "M" channel.

M-type channels are able to conduct a non-inactivating outward current with a threshold of about −60 to −80 mV and regulated by many neurotransmitters such as SP and bradykinin. The biophysical features of this current include slow activation and deactivation potassium current. Because M channels can be opened near the resting membrane potential, they also play a role in clamping the resting membrane potential, so they are ideally suited to control neuronal excitability.

M channels are functionally expressed in various central and peripheral neurons including hippocampal [100] and DRG neurons [101]. *KCNQ2*, *3*, and *5* are variably expressed in sensory neurons, including small-diameter nociceptors and large-diameter proprioceptors. Because pathological pain such as inflammatory and neuropathic pain features for neuronal hypersensitivity responds to nociceptive inputs, M-type potassium channels are considered a potential analgesic target in controlling nociceptive excitability. Opening of M channels results in hyperpolarization of the neurons, which decreases cell membrane excitability. Accordingly, the M-channel openers retigabine and flupirtine can effectively attenuate muscle pain [102] and inflammatory pain [101].

In 2012, Lin and colleagues showed that SP-enhanced M channel activity in muscle-afferent DRG neurons via an unconventional signal pathway by activating NK1R coupled with phosphotyrosine kinase to attenuate the mechanical hyperalgesia [57]. Then, Gamper's group demonstrated that SP could augment the M channel in a subset DRG neurons mainly by acting on NK1R via Gi/o and a redox-dependent pathway [76]. The similar result but discrepant cellular mechanisms could be due to the different subset of DRG neurons examined. The SP-enhanced M current via the phosphotyrosine kinase pathway is prominent on medium to large DRG neurons expressing ASIC3 innervating muscle, whereas the SP-enhanced M current via the Gi/o pathway acts mainly on small neurons expressing TRPV1 innervating skin.

These studies provide insight into SP-mediated anti-nociception in local tissues. Activating the SP-NK1R pathway specifically in muscle afferents becomes an attractive therapeutic target to treat chronic pain. Although the pro-nociceptive effect of SP in the spinal cord has been well documented, local peripheral application of SP can be diluted and has little effect on the spinal cord. Thus, targeting the SP-NK1R pathway in the PNS creates a strategy for pain relief without producing severe side effects in the CNS.
