Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage . The sensation of pain is a protective mechanism that makes us aware of injury and disease. Nociceptors are receptors present at sensory nerve terminals that mediate the sensation of pain through their ability to detect harmful or potentially harmful (noxious) stimuli. Damage caused by a noxious stimulus causes the release of substances such as protons, ATP, bradykinin, and serotonin and these activate nociceptors.
Activation of a nociceptor generates a nociceptive signal. This electrical signal is transmitted along the axon of the sensory neuron to the cell body in the dorsal root ganglion (DRG), and from here to the pre-synaptic terminal in the dorsal horn of the spinal cord. At the pre-synaptic terminal neurotransmitter release occurs and this modulates the nociceptive signal which is then forwarded to secondary neurons and then up to higher centres in the brain where it is interpreted as pain .
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Sensory nerves are classified according to their diameter and the level of myelination . Nociceptive axons consist of small diameter sensory nerve fibres and two distinct types exist: myelinated, fast conducting AÎ´ fibres and unmyelinated slowly conducting C fibres. These fibres are responsible for the sensation of immediate, sharp, intense pain and persistent, dull burning pain respectively .
Various ion channels have been identified which are involved in nociceptive signalling (see figure 1). There has been extensive research into the role of voltage-gated sodium channels (VGSCs) in neuronal excitability and their involvement in nociceptive signalling and therefore this essay will particularly focus on VGSCs. However, there are many other voltage-gated channels that have an important role in nociceptive signalling and these will be considered briefly.
As previously mentioned a nociceptive stimulus causes the release of substances which activate nociceptors. There are a number of chemically-sensitve ion channels which can detect the various chemicals and contribute to nociceptive signalling and some of these will also be considered.
Figure 1 examples of ion channels present on
sensory neurons (from Ref. 3)
Detection and initiation of Pain
There are different types of noxious stimuli which can induce pain. Examples include: mechanical stimuli caused by applying strong pressure for example from a sharp object, thermal stimuli caused by extremes of temperature and chemical stimuli which detect various chemicals and changes in pH .
The Transient Receptor Potential Channel (TRP) family of receptors are activated by noxious heat (> 43Â°C) stimuli. Six channels have been identified in this family, and each exhibits distinct temperature activation. The TRPV1 receptor (capsaicin receptor) is expressed at nociceptors in sensory neurons and has been suggested to play a role in thermal nociception . TRPV1 channels are activated by noxious heat, capsaicin (ingredient of hot chilli peppers), acid and bradykinin, among others. A schematic of the nociceptive signalling pathway initiated by capsaicin or heat on the TRPV1 receptor can be seen in figure 2. TRPV1 channels are upregulated in inflammatory conditions  and this suggests that TRPV1 channels may play a role in the development of inflammation.
As TRPV1 channels are suggested to be responsible for inflammation they play a significant role in the generation of nociceptive signals. This is because inflammation causes the release of chemicals such as bradykinin, serotonin, K+, H+ and ATP. In the periphery, ATP is released as a result of inflammation and can excite primary afferent nociceptors by acting on P2X receptors , a family of ATP sensitive receptors
Figure 2. Nociceptive pathway due to TRPV1 activation
(from Ref. 2).
In the central nervous system (CNS), ATP released from nociceptive afferents or second order neurones, can modulate neurotransmitter release or activate post-synaptic neurones, mediating central nociceptive transmission  via P2X receptors. P2X receptor subtype P2X3 is highly expressed in the DRG  and upregulation of this channels has been reported in animal models of neuropathic pain . Blocking this channel using a selective P2X3 antagonist, A-317419, was found to reduce chronic pain . Therefore there is good evidence that P2X receptors also play a role in the modulation of nociceptive signalling.
Tissue injury and Inflammation are associated with local acidosis and acidity plays a role in nociception. The mechanical threshold of the skin decreases as the pH becomes acidic and it has been shown that there is a dose response relationship between pH and firing frequency . The acid sensing ion channels (ASICs) are a family of sodium channels which detect tissue acidosis and are involved in pain signalling. Six isoforms of ASICs have been discovered and out of these, ASIC3 is thought to have the greatest involvement in pain detection as it is highly expressed in the DRG. This isoform is also thought to be involved in inflammatory related allodynia and hyperalgesia.
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Generation of Nociceptive signals
The generation of an action potential is the initial step in nociceptive signalling. The different phases arise due to different combinations of ion channels and the different phases can be seen in figure 3.
Voltage-gated sodium channels (VGSCs) are highly expressed in sensory neurons and allow a rapid influx of sodium ions. This generates an inward sodium current which forms the depolarising upstroke of the action potential. VGSCs open (activate) for only a few milliseconds due to an increase in membrane potential.
Figure 3 Phases of an action potential. In a sensory neuron,
resting membrane potential is approximately -80 mV.
The current through the channel will cease after a further few milliseconds and the channel will close rapidly by a process termed fast inactivation. The channel will only open again when it has returned to a resting state and therefore recovery from inactivation will influence the number of action potentials that can be generated at the sensation of pain.
The role of sodium channels in nociceptive signalling has been known for some time, as it is possible to reduce or prevent pain with sodium channel blockers such as lidocaine. Voltage-gated sodium channels are a family of nine structurally related channels (Nav1.1-Nav1.9) which differ in the composition of their Î±-subunits. A single Î±-subunit forms the channel pore and contains the voltage sensor responsible for voltage-gating. It can be functionally expressed on its own but it is generally associated with Î²-subunits, which modify the kinetics and voltage dependence of the channel .
The Î±-subunits display a distinct pattern of expression and can be characterised by their sensitivity to tetrodotoxin (TTX), a toxin isolated from puffer fish. Most sodium channels are blocked by this toxin, which binds to the channel pore, and are referred to as TTX sensitive channels (TTXs). Sodium channels containing the Nav1.5, 1.8 and 1.9 Î±-subunits are not blocked by TTX and are said to be TTX resistant (TTXr).
Sensitivity to TTX divides the channels into two distint types: TTXs and TTXr. The proportion of each type of channel in a neuron will therefore determine the excitability of that particular neurone. TTXs channels tend to inactivate at hyperpolarized membrane potentials whereas TTXr channels require membrane depolarization to inactivate . This means that TTXr channels will inactivate much quicker than TTX-sensitive channels which will mean that neurons with a higher degree of TTXr channels can fire more action potentials and produce an increased pain signal than neurons with more TTXs channels.
The difference in sensitivity to TTX suggests that the sodium channel subunits have different kinetics and differ in their contribution to various pathological states. This is true as only three sodium channel subunits: Nav1.7, Nav1.8 and Nav1.9, have been described in small sensory neurons and play a role in nociception. From electrophysiological studies Nav1.7, Nav1.8 and Nav1.9 channels were found to produce sodium currents with distinct biophysical properties . Modulation of these currents as a result of axonal injury during acute pain can lead to an increase in sodium channel expression and conductance which can result in a random pattern of repetitive spike firing activity .
The Nav1.7 sodium channel is a TTXs channel and has been identified in 85% of functional nociceptors . Nav1.7 produces a fast activating and inactivating current , however due to its slow rate of recovery from fast inactivation it is thought that this channel might act to set the threshold for action potential generation . There is evidence that changes to Nav1.7 channel gating properties can lead to increased pain sensations. The Nav1.7 channel is encoded by the SCN9A gene and there are three pain syndromes linked to mutations in this gene. There are two gain of function mutations: Inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD), and the loss of function mutation which gives rise to congenital insensitivity to pain (CIP). Details of these disorders can be found in table 1.
Table 1 Details of pain disorders caused by SCN9A gene mutations.
Disorder Symptoms Properties
Inherited Erythromelalgia Episodic attacks of burning Hyperpolarised shift in the
pain in hands and feet in voltage dependence of
response to mild warmth activation. Lower threshold
[16,17] for action potential firing and firing at higher-than-
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Normal frequencies in
response to suprathreshold stimuli [18,19]
Paroxysmal Extreme Pain Severe burning rectal pain. Depolarizing shift in the
Disorder sometimes accompanied by voltage dependence of
non-epileptic seizures, steady state inactivation.
syncopes and bradycardia Leads to incomplete
[20,21]. activation of the channel
and prolonged persistent
Congenital insensitivity to Inability to experience pain Expression in mammalian
Pain. Some patients also experience cells failed to produce
Inability to smell. functional Nav1.7 currents.
This information highlights the importance of the Nav1.7 in the generation of pain, as certain mutations in this channel result in the inability to experience pain and small alterations can lead to conditions of sever chronic pain.
There is also evidence that the Nav1.8 channel is associated in pain signalling. These channels are highly expressed in the dorsal root ganglion and in trigeminal neurones [22, 23] which are known to be involved in pain signalling. Nav1.8 channels produce a TTXr current which displays slow rates of activation and fast inactivation and the voltage-dependence is more depolarised that TTXs currents. This means that Nav1.8 channels are likely to be activated after TTXs channels, and are unlikely to contribute to the action potential generation threshold. Through animal studies it has been shown that Nav1.8 is largely responsible for most of the upstroke of the action potential [24, 25]. Therefore these channels can greatly influence neuronal excitability. "The depolarised voltage-dependence of fast inactivation displayed by these channels contributes to the continuous firing of action potentials during sustained depolarisations ." This is important in neurones at the site of injury in which the membrane potential will be more depolarised .
The role of Nav1.8 in inflammatory pain was discovered through animal studies using Nav1.8 null mice. These mice were reported to show reduced responses to inflammatory agents such as carrageenan, NGF and capsaicin. Normally these substances induce hyperalgesia, an increased senstitivity to painful stimuli and allodynia, where pain is produced by stimuli that are not normally painful. As these mice display reduced responses to such chemicals this demonstrates the involvement of Nav1.8 in inflammation.
Voltage-gated potassium channels (Kv) are responsible for the repolarising phase of the action potential. Opening of Kv channels results in an influx on K+ ions into the cell and this decreases excitability returning membrane potential to its resting state. Kv Channels are highlighted as potential therapeutic targets as there ability to decrease excitability suggests that they could modulate pain transmission.
Transmission and modulation of nociceptive signals
After an action potential is generated due to a noxious stimulus this electrical signal is transmitted along the axons of sensory neurons to the cell body in the DRG and then to pre-synaptic terminals in specific laminae of the dorsal horn in the spinal cord. The two types of axons involved in nociceptive signalling are unmyelinated C-fibres and myelinated AÎ´ fibres (described previously). In C fibres the nociceptive signal is transmitted via VGSC present along the length of the axon via action potential conduction. AÎ´ fibres are designed for fast transmission due to myelination and transmission occurs at breaks in the myelin sheath called nodes of ranvier. VGSCs are concentrated at the nodes of ranvier and mediate saltatory conduction. There is evidence that Nav1.6 channels are the predominant form found at the nodes of ranvier in both the peripheral and central nervous systems . Nav1.8 has been reported to be present at the nodes of ranvier in 20% of neurons in the tooth pulp  and also in unmyelinated axons of DRG  and trigeminal ganglia .
In nociceptive neurones, Ca2+ entry through voltage-gated calcium channels (VGCCs) is essential for nociceptive transmission. VGCCs are significant components at the pre-synaptic terminals of sensory neurons and modulate neurotransmitter release. There are five different types of VGCC: L type, N type, P/Q type R type and T type . The N-type VGCC is thought to be critical for the transmission of nociceptive signals [31, 32]. They are present in the cell body of DRG neurones  which project to superficial laminae in the the dorsal horn of the spinal cord and synapse on secondary neurones . N-type calcium channels were identified in nerve terminals in the laminae in the dorsal horn via autoradiography and immunohistochemistry techniques.
L-type and T-type calcium channels are also thought to be involved in nociception. This is because the L-type channel blocker nifedipine inhibits the release of substance P induced by inflammation  and L-type channel blocke verapamil reduces mechanical and thermal pain . Similarly T-type channel blockers produce an analgesic response due to noxious stimuli.
N-type calcium channels are suggested to mediate neurotransmitter release at the pre-synaptic terminal which acts on post-synaptic terminals of secondary neurons. Examples of neurotransmitters released include glutamate and other excitatory amino acids (EAAs), and the neuropeptides substance P and cacitonin gene related peptide (CGRP). These bind to post-synaptic receptors on secondary neurones. EAAs act at both metabotropic and ionotropic receptors. The major ionotropic receptors in the dorsal horn are DL-a-NH2-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors. Activation of these receptors permits the conduction of ions through the opening of cation permeable channels. NMDA receptors can conduct both calcium and and sodium ions and AMPA receptors are predominantly selective to sodium ions. The influx of cations as a result of receptor activation will depolarise the postsynaptic neurone. This increases excitability and results in transmission of the nociceptive signal to the brain where it is interpreted as pain.
There are many ion channels involved in the nociceptive pathway and within each class there are numerous subunits and subtypes. Thus deciphering the role of each is a massive and somewhat impossible task. The signalling process is equally complex and for this reason there are many cases of chronic and neuropathic pain which are not understood. There has however been huge advances in pain research, particularly in the discovery that deficits in the sodium channel Nav1.7, result in the inability to detect pain. Selective targeting of this channel pharmacologically could lead to the development of novel analgesics that are selective to this subunit and this is an exciting area of current research. The chemically gated ion channels are also heavily involved in nociceptive signalling and also have the potential as therapeutic targets.