Chronic pain affects approximately one-sixth of the population at some time in their lives. Pain usually results from tissue damage, but in some diseases spontaneous pain can occur: this pain is independent of any tissue injury. Spontaneous pain can be devastating and remains very hard to treat because its underlying mechanisms are not understood. Recently, we discovered that the degree of spontaneous pain is related to the rate of spontaneous firing of action potentials (nerve impulses) in a subpopulation of pain-sensing neurons. We aim to clarify the underlying mechanisms of these spontaneous impulses.
Nerve impulses normally carry information from sensory receptors in the skin towards the central nervous system. These impulses signal touch, temperature or pain; normally pain signals result only from actual or threatened tissue damage, but spontaneous impulses in pain-signalling nerve fibres will produce a sensation of pain. Nerve impulses are generated by protein molecules (ion channels) that regulate the flow of ions (mainly sodium and potassium) across the membrane. Potassium ions move outwards, making the nerve more negative inside and reducing the likelihood of impulses being generated. In contrast, sodium ions move inwards, making the nerve more positive inside and increasing the tendency to fire impulses.
This proposal focuses on ion channels that are open under resting conditions and allow potassium ions to leave the nerve fibre (through subtypes known as A-type and M-type potassium channels) or sodium ions to enter (through a channel subtype known as HCN). The hypothesis is that reducing expression or activity of A- or M-type channels, and/or increasing expression or activity of HCN channels, would increase the tendency of a pain-signalling nerve fibre to generate spontaneous impulses and thus create the sensation of pain.
We shall test this hypothesis by recording electrical currents and voltage changes caused by these channels in sensory neurons in rat in vivo. We aim to determine in animal models of chronic pain whether spontaneous firing and spontaneous pain behaviour are affected by blocking or opening these channels with pharmacological agents. We shall also dye-inject spontaneously active neurons enabling us to use labeled antibodies to detect which proteins (including ion channels) are being expressed in these neurons, and to determine whether expression of these ion channels is altered by agents causing inflammation which are known to increase spontaneous impulse generation.

Technical Abstract:
Spontaneous/ongoing pain, being unavoidable, is a debilitating aspect of many chronic pain states. It is the primary complaint of neuropathic pain patients but it is refractory to current analgesics because its underlying mechanisms are poorly understood. Although spontaneous pain seemed likely to be caused by spontaneous activity (SA) in nociceptive dorsal root ganglion (DRG) neurons, until recently this had not been shown. We 1 were the first to relate putative spontaneous pain behaviour with spontaneous firing frequency; this was seen both after spinal nerve injury and tissue (hindlimb) inflammation. Neurons involved were uninjured (intact) C-fibre nociceptors in both situations and A?-fibre nociceptors during tissue inflammation but not after nerve injury. The underlying ionic and molecular mechanisms of SA in these intact nociceptors have not been studied.
Ion channels that are active near resting potential (Em) are likely to contribute to SA generation because such ion channels affect the probability of SA generation by altering membrane potential and stability. K+ channel candidates that normally clamp/stabilize the membrane potential near Em include the Kv1.4 and/or Kv4.2 channels that carry A-type K+ currents and KCNQ/Kv7 channels that carry M-type K+ currents. Other candidates active near Em are the HCN channels that carry the nonselective hyperpolarization-activated (Ih) current. Since the effect of Ih/HCN channels is to oppose the actions of the outward K+ currents, an increase in their expression and/or function during chronic pain states may drive the membrane potential towards the threshold of AP generation and thereby cause spontaneous firing.
Our aim is to test, in animal models of chronic pain, the hypothesis that these channels make an important contribution to the generation of SA in nociceptors and spontaneous pain behaviour by examining a) changes in their expression and function, b) the influence of activating or blocking them and c) influences of pro-inflammatory mediators on channel expression and function. To achieve this aim, we shall use several intracellular recording approaches, in rats, including: a) in vivo voltage clamp technique, b) in vivo voltage recordings, dye injection and immunocytochemistry and c) pharmacological studies in a perfused decerebrate preparation. These approaches will be on normal and in neuropathic and inflammatory pain models, and will be coupled with pain behavioural tests. The work will help determine which of the ion channels could become a target for designing novel therapies for chronic spontaneous pain.