Persistent pain: the contribution of NaV1.9

Sodium channels are crucial to the ability of sensory neurones to fire action potentials. Modulation of these ion channels can cause neurones to become sensitised leading to a state called hyperalgesia. A recent article by Ostman et al. demonstrates that the decreased inflammatory hyperalgesia observed in NaV1.9 knockout mice is due to the lack of upregulation of a persistent sodium current in sensory neurones by GTP-gamma-S. In neurones from wild type mice this upregulation causes a negative shift in sensory neurone threshold activation: sensitisation. This short article reviews the set of experiments that brought about this finding

Pain channelopathies

Pain remains a major clinical challenge, severely afflicting around 6% of the population at any one time. Channelopathies that underlie monogenic human pain syndromes are of great clinical relevance, as cell surface ion channels are tractable drug targets. The recent discovery that loss-of-function mutations in the sodium channel Nav1.7 underlie a recessive pain-free state in otherwise normal people is particularly significant. Deletion of channel-encoding genes in mice has also provided insights into mammalian pain mechanisms. Ion channels expressed by immune system cells (e.g. P2X7) have been shown to play a pivotal role in changing pain thresholds, whilst channels involved in sensory transduction (e.g. TRPV1), the regulation of neuronal excitability (potassium channels), action potential propagation (sodium channels) and neurotransmitter release (calcium channels) have all been shown to be potentially selective analgesic drug targets in some animal pain models. Migraine and visceral pain have also been associated with voltage-gated ion channel mutations. Insights into such channelopathies thus provide us with a number of potential targets to control pain

Role of the hyperpolarization-activated current Ih in somatosensory neurons

The hyperpolarization-activated current (Ih) is an inward current activated by hyperpolarization from the resting potential and is an important modulator of action potential firing frequency in many excitable cells. Four hyperpolarization-activated, cyclic nucleotide-modulated subunits, HCN1–4, can form Ih ion channels. In the present study we investigated the function of Ih in primary somatosensory neurons. Neuronal firing in response to current injection was promoted by elevating intracellular cAMP levels and inhibited by blockers of Ih, suggesting that Ih plays a critical role in modulating firing frequency. The properties of Ih in three size classes of sensory neurons were next investigated. In large neurons Ih was fast activating and insensitive to elevations in cAMP, consistent with expression of HCN1. Ih was ablated in most large neurons in HCN1−/− mice. In small neurons a slower activating, cAMP-sensitive Ih was observed, as expected for expression of HCN2 and/or HCN4. Consistent with this, Ih in small neurons was unchanged in HCN1−/− mice. In a neuropathic pain model HCN1−/− mice exhibited substantially less cold allodynia than wild-type littermates, suggesting an important role for HCN1 in neuropathic pain. This work shows that Ih is an important modulator of action potential generation in somatosensory neurons