Polymodal Nociceptors

Nociceptors are free nerve endings in the afferent peripheral nervous system (PNS) that selectively respond to different stimuli. The differences are related to the stimulus which they respond to and the properties of the nerve fibers associated with them. There are three types A, B and C groups based on their diameter. There are numerous types of nerve fibers that have nociceptors. These are the free endings at the

Average pain is processed by nociceptors via two sets of neural pathways. The ascending neural pathway is activated by painful stimuli like extreme temperature, pressure, and impact. The ascending pathway sends nociceptive signals to send neurotransmitters

is known about the mechanisms of the CNS. This review focuses on the Peripheral Nerve Injury and

Peripheral nerves are bundles of nerve fibers that exit the spinal cord individually or via two main plexuses known as the brachial plexus and the lumbosacral plexus. Peripheral nerve fibers transmit sensory and motor information between the body and the central nervous system (brain and spinal cord) through ventral and dorsal roots. Axons of motor neurons innervate muscles to produce both voluntary and involuntary movements. On the other hand, sensory axons make connections with sensory receptors in the skin to detect pain and sensation.

There are many mechanisms for the sensitisation of nociceptors. A common scenario for this occurrence is when peripheral tissue is subjected to exogenous injury, whether it be mechanical, chemical, or toxic. Injury results in localised increase in inflammatory mediators, leading to the sensitisation of nociceptors. Upregulation and increased expression of various membrane receptors is the most common mechanism. Ionotropic receptors, Gq protein-coupled metabotropic receptors, Gs protein-coupled metabotropic receptors, and mitogen-activated protein kinase have been shown to be upregulated in nociceptors in response to the presence of inflammatory mediators (Sessle ed 2008). The resultant effect is increased conductance, lowered threshold for the initiation of action potentials, spontaneous depolarisation, and increased after-discharges to supra-threshold stimuli (Sessle ed 2008). Sprouting, or the growth of neuronal axons into the damaged tissue, also contributes to pathological pain. Increased number of nociceptive axons increases the opportunity for spatial and temporal summation and activation of nociceptors, which under normal conditions would not be activated. Sufficient concentration of inflammatory mediators can also lead to the activation of nociceptors which do not participate in the detection of noxious stimulus (Sessle ed 2008). With an increased number of nociceptors feeding back to the CNS, the sensation of pain is

Serotonin (5-HT) and norepinephrine are primary neurotransmitters of the monoamine pathway and have been implicated in chronic pain (Bardin, 2011). These monoamines, particularly in areas such as the PAG, form a depression-pain interface. The PAG takes information sent from the amygdala, neocortex, and hypothalamus, processes the information, and then sends the modified signals to the brainstem, particularly the RVM (Millan, 2002). Approximately 20% of the neurons within the RVM are serotoninergic. Depending on the receptor, dose, and chronology, 5-HT within the CNS can be either pro- or antinociceptive (Bannister et al., 2009). As such 5-HT's influence on pain modulation can be quite complex.

They found that nerve impulse acts like a gate when there is a perceive pain. It has thought that the Substantia Gelatinosa in the dorsal root horn acts as gate for all pain. When there is not pain, the inhibitory neuron within the dorsal root stops impulses going to the brain, which means the gate is closed. Normal input happens when the larger fibers stimulate the inhibitory neuron, but they prevent the projection neurons, which is what stimulates the brain to perceive pain. Pain reception happens when there are more c fibers or the small fiber stimulating the inhibitory neuron than the larger fibers. The projection neurons send a signal to the brain, which will in turn cause the gate to open, and pain is perceived. Diagram B in the appendix to the paper illustrates the concept. The gate can be open by physical factors (bodily injury), emotional factors (depression), or behavioral factors (attention to the injury and concentrating on the pain). Likewise the gate can be close by physical factors (analgesic remedies), emotional factors (being in a good mood), and behavioral factors (not focusing on the

Pain is the sensation that we perceive to be unpleasant, which leads to behavioural change to prevent further damage and to assist in recovery. Sensory information is detected at the peripheral nerve terminals situated at the epidermal layer of the skin, which then coveys the information to the spinal cord to promote ‘spinal withdrawal reflexes’. The information is passed along primary afferent fibres and there are three different types, which determine the intensity of the sensation. The three different types of primary afferent fibres are Aβ, Aδ, and C where each type varies in the degree of myelination and its overall diameter. The greater the diameter and more myelination present on the fibre will lead to a sharp feeling of pain as it generates a fast action potential. Hence, as Aδ fibres have a bigger diameter and more myelination it is the first sharp pain

The first stage of nociception is transduction, this is the perception of a noxious (damaging) stimulus, which activates high threshold nociceptors through multiple mechanisms, such as, thermal (heat), mechanical (ligaments being stretched) and chemical. With chemical activation, infection creates inflammation around the wound to promote healing, some chemicals produced trigger nociceptors (sometimes constantly) and some lower threshold of activation for other nociceptors (Basbaument et al 2009) meaning a person can often feel more pain. The second stage of nociception is transmission; this is where the information detected is sent to brain by specialised nerve pathways. Aδ fibres are fast and specific, due to them being myelinated and unimodal (they respond to a specific type of pain per fibre) and C fibres conduct slow sensation as they are unmyelinated and polymodal (responding to multiple types of pain per fibre). The final stage of nociception is interpretation, this is where the brain processes painful stimuli and decides if it should be acted on (if there is a danger). It is only at this point that pain can be felt. Nociceptors do not send a pain signal but instead alert the brain to

The parasympathetic ganglia are much more widely distributed than the sympathetic branch ganglia. Drawn in the diagram previously, the nerve fibres originate at either end of the spinal cord, near the organs they affect. However, because the fibres are less

The modern era in neuromodulation for the treatment of pain has started after the seminal work of Melzack and Wall, who described the so-called gate control theory (Melzack and Wall 1965). The first application of neuromodulation in a chronic pain patient was performed by Shealy in 1967 (Shealy, Mortimer et al. 1967). SCS has become a valuable method to treat chronic neuropathic pain. Traditionally, SCS consisted of an electrode placed on the dorsal columns of the spinal cord.

Transient receptor potential (TRP) are ligand-gated controlled ion channels that function in the process of nociception where transmission pain signals by nociceptors are carried as impulses from the sensory nerves to the central nervous system through afferent neurons (Dai 2016; Marwaha et al., 2016). Nociceptors, also called noxious stimulus detectors, are pain sensory receptors made up of myelinated and unmyelinated neuron fibers that relay action potentials to the central nervous system (CNS) and peripheral nervous system (PNS), which are interpreted as pain (Woolf et al., 2007). Transient receptor potentials detect chemical or physical stimuli that trigger nociceptor activation that result in pain perception (Marwaha et al., 2016). The TRP channels control physiological perception of temperature, taste, pheromones and painful mechanical sensory inputs, which is accomplished through six different TRPs (TRPV1, TRPV2, TRPV3, TRPV4, TRPM8, and TRPA1) (Dai 2016; Marwaha et al., 2016). Interestingly, all six TRP channels of the three TRP family types are expressed in afferent pain sensing nociceptors (Dai 2016; Marwaha et al., 2016). This suggests that all six of the TRP channels are involved in pain perception. The afferent nociceptors are hyper-activated in diseases including neuropathic pain and peripheral inflammation. Recent findings suggest that TRP channels function in a critical position with the association of these diseases. Researchers are exploring novel

Due to the anterolateral tract in the spinal cord, which controls the processes of pain and touch, there would be absence of light touch, vibration, and position of sense ipsilateral, below the area of trauma. Loss of bladder and bowel control may be a symptom. Damage to the lateral corticospinal tract causes paralysis on the same side of the injury (Monoplegia), and damage to the lateral spinothalamic tract causes absence of pain and temperature sensation on the contralateral side of the body to which the trauma occurred.

Large, fast-conducting fibres (α and β fibres) inhibit small, multi-synaptic, slow-conducting fibres (C-fibre) at the dorsal horn.13 Gaps were missing within this research due to available research resources; Noordenbos13 was unable to investigate past the spinal cord. This statement was unexplained yet it was a development in pain research. Melzack and Wall2 developed the pain-gate theory based from the research by Noordenbos13. The theory explained what Noordenbos13 was unable to prove; impulses are projected to the brain via the dorsal column, where central processes influence the activity of the gate-control system.2

Nociception defines as the detection mechanisms of noxious stimuli by the primary afferent nociceptors of the peripheral nervous system (National Research Council, 2009), encoding and transferring by the central nervous system (Barrot, 2012). Noxious stimuli activates nociceptors that are in the periphery and enters in the dorsal horn of the spinal cord via dorsal root ganglion, ascends to the thalamus via spinothalamic tract. Nociception can happen without pain. Pain is an unpleasant sensory product of higher brain centre (National Research Council, 2009), often associated with potential tissue damage (Barrot, 2012).