Physiology – How the Body Detects Pain Stimuli

Home , Noxious stimulus, Stimulus (physiology)

Keywords: Pain/Analgesia/Nervous Nursing Practice system/ Stimulus Review ●This article has been double-blind Pain management peer reviewed The first of a three-part series on the management of pain describes how pain is detected in the body and the implications for clinical practice

part 1 of 3: Pain management Physiology – how the body detects pain stimuli

In this article... 5 key An overview of the pain pathway points Pain (noxious) How pain receptors detect pain 1stimuli may be How agonists and antagonists are used to manage pain mechanical, thermal or chemical Author Amelia Swift is senior lecturer at neuropathy), or to a change in the way the The threshold the University of Birmingham, Institute of nervous system detects and manages sen- 2of activation of Clinical Science sory signals (as is the case in chronic low pain receptors Abstract Swift A (2015) Pain management back pain). varies throughout 1: how the body detects pain stimuli. Acute pain is best relieved by inter- the body, with the Nursing Times; 111: 39, 20-23. rupting pain signals as they travel cornea in the eye Pain is the body’s way of telling us between their source and the brain, or by being more something is wrong. It has a sensory and boosting the body’s own efforts to alle- sensitive than the emotional component. This three-part viate pain such as the production of neu- skin, for example series focuses on acute pain, describing roactive chemicals like endorphins. The frequency the physiology of a normal and well- Chronic pain can be more difficult to 3a nociceptor behaved pain pathway and how this manage because of differences in the sig- fires relates to the relates to commonly used pain- nalling process. Therefore the starting pain intensity; a management strategies. This first article point for being able to provide effective higher frequency introduces the pain system and how the pain management is an understanding of means a greater body detects a threatening (noxious) the “normal” pain pathway associated pain intensity stimulus. Part two describes how that pain with acute pain. A glossary of terms is Analgesics message is transmitted to the spinal cord provided in Box 1 (page 23). 4such as and the brain, and the response of the morphine act as brain to the stimulus. The third article An overview of the pain system agonists, binding discusses the assessment of pain. Acute pain is a sensation triggered by a to the pain threatening (noxious) stimulus to the skin receptor and so ain is defined as an unpleasant (cutaneous pain), the musculoskeletal preventing it from sensory and emotional experi- system, or the internal organs (visceral firing a pain signal ence associated with actual or pain), which is then signalled to the brain Painkillers such Ppotential tissue damage or so it becomes aware of the threat and can 5as capsaicin described in terms of such damage decide how to respond (fight or flight). cream work by (Merksy and Bogduk, 1994). As a physical The signal may trigger a reflex response overstimulating a sensation pain usually signals a danger to that causes us to move out of range of the particular receptor, the body from an internal or external stim- threat. The pain “system” comprises a which is then spent ulus such as an infection or a knife wound. number of elements that detect the and will not fire for This type of pain is called physiological noxious stimulus, convert it to an electrical some time pain or acute pain and normally resolves signal and transfer that signal rapidly to afterwards once the stimulus has been removed and the spine and then the brainstem and the damaged tissues have healed. Chronic finally the cortex. These are illustrated pain, on the other hand, continues indefi- in Fig 1. nitely and might be related to an ongoing The basic elements of the pain pathway disease process such as osteoarthritis, are different kinds of sensory nerves that damage or dysfunction of the nervous connect the tissues to the spinal cord and system (as is the case in painful diabetic run together in bundles between the two.

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FIG 1. basic elements of the pain pathway

Cell body Cells in the tissues Axon of sensory nerve ﬁbre

Direction of signal Pre-synaptic Terminals of terminal of sensory sensory ﬁbre nerve ﬁbre

Secondary neuron

Brain

Axon of secondary neuron

Acute pain is caused by activating pain receptors throughout the body

Each sensory nerve terminates in a multi- » Chemical: acids, alkalis, irritants, (or noxious stimuli) are found at the nerve tude of specialised receptors that are capsaicin (active ingredient of endings of primary afferent A-delta and C spread across the skin and organ tissues; chilli peppers); fibres (Table 1). Primary afferent A-beta these connect by a long axon to their cell » Thermal: heat (above 42°C), cold fibres respond to non-noxious stimuli, body (which lies just outside the spinal (below -15°C); such as touch. cord). The cell body has a second axon that » Mechanical: punctate (sharp) pressure, A mechanical stimulus, such as an terminates in the dorsal horn of the spinal rotation beyond normal functional over-stretch of a muscle fibre or over- cord. The sensory nerve responsible for range (for example joints), distension rotation of a joint, causes receptors on the detection of a threat is the first step in the (for example, bowel). surface of the nerve ending to stretch. pain pathway and is called the primary A noxious stimulus is detected by Noxious heat or cold near the nerve ending afferent fibre (PAF). Afferent means sig- receptors that are situated on the cell and noxious chemicals interact with nals travel along it towards the spinal cord. membrane of the sensory nerve ending. specific receptors. The receptor responds Once the primary afferent fibre termi- The receptors are proteins that are made in to the triggering event chemically in one of nates in the spinal cord, it makes chemical the cell body of the nerve and then trans- three ways: and physical connections with other cells ferred to the surface of the nerve ending. » Agonism/excitation: the electrical including secondary neurons. The signal The types of receptors on the sensory nerve potential of the cell is raised above the is passed from the primary afferent fibre ending determine the type of stimulus that activation threshold and an action to the secondary neuron, which carries the nerve cell can respond to, and there are potential is initiated; the signal to the brain. It is not until the many types. The receptors that detect pain » Sensitisation: makes it easier for the signal reaches the cortex that the brain becomes aware of the pain. Table 1. Types of sensory afferent fibre Detection of a noxious stimulus Pain can be detected (or sensed) in most of Fibre Size Relative Myelin Stimulus type Alternative the body’s tissues except in healthy carti- speed name lage and the brain itself. The key elements C Small Slowest None ● Mechanical CM involved in detection are: ● Mechanical and heat CMH » A threatening or harmful (noxious) ● Mechanical, heat and stimulus; chemical Polymodal » Units that can respond to different ● In inflammation only noxious stimuli (sensory nerve endings – mechanical, heat and Silent with receptors). chemical Noxious stimuli are traditionally A-delta Medium Medium Light ● Mechanical and heat AMH divided into three categories: chemical, ● Mechanical and cold thermal or mechanical. To initiate a pain ● High-threshold AMC signal, the stimulus has to be above a par- mechanical ticular intensity (threshold) that would be AHTM enough to cause damage to the tissues. A-beta Large Fastest Yes ● Low-threshold mechanical LTM Examples of these include: Lamb Peter Alamy,

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FIG 2. relatively small quantity of positive ions; creation of an action potential this will not be enough to trigger an action potential.

Oscilloscope Significant tissue damage causes lots of agonists, so the nerve cell will achieve its Sensory 2. Agonist nerve activates action potential threshold, and will do so a ending receptor number of times in quick succession. This means the nerve will fire frequently (for Intracellular ﬂuid example 50 action potentials per second) – this creates high pain intensity. Less Electrode frequent firing (for example one action Extracellular 1. Tissue damage potential per second) will produce a lower ﬂuid breaks cells intensity of pain if it leads to pain at all. The maximum number of action

Tissue cells potentials that a sensory fibre can achieve is about 100 per second (Bear et al, 2001). The action potential is then rapidly transmitted along the axon until it reaches Ion Action the sensory nerve fibre terminal in the channel potential opens achieved dorsal horn. Once an action potential has been cre- ated the nerve cell actively pumps positive ions back out into the extracellular fluid in order to return to its resting potential. These excitable nerve cells can be compared to a bottle of cola: they sit quietly fizzing, and while they have the potential to do something an input of energy is needed. If a soft mint sweet is added to the bottle, action potential is reached and the fizz is no longer quiet but loud and has cell to achieve its threshold for action axons by the movement of electrically enough energy to carry cola out of the potential generation; charged ions. To initiate this process the bottle and into the air. » Antagonism/hyperpolarisation: makes interior of the nerve cell has to change In the cola scenario you are the stim- it more difficult for the cell to achieve from being negatively charged (about ulus and you interact with the cell by its threshold for action potential -65mV) to positively charged. This is called removing the cap (opening an ion generation. depolarisation. channel). The mint sweet represents the The interaction of agonists with recep- positive ions. If you dropped a very small Implications for practice tors causes changes in the cell membrane portion of the sweet into the bottle you Mu (μ) receptors are found on the sensory – opening up pores called ion channels would still see a reaction but not enough to nerve endings in the peripheral nervous that allow positive ions (sodium and cal- cause the explosion – you did not reach the system as well as in the spinal cord, the cium) to enter the nerve cell. As the posi- activation threshold. brain, the gut and many other places. tively charged sodium and calcium ions A larger quantity of the mint would When an opioid drug, such as morphine, move into the cell it becomes more posi- cause a larger reaction. There comes a binds to a mu receptor it acts as an antago- tively charged. This continues to a peak of point where there is “enough” of the sweet nist and makes it more difficult for the around 55mV, which is called the activa- and the large reaction cannot be prevented. nerve cell to become excited (Marvizon et tion threshold. This is the activation threshold and the al, 2010). Giving morphine by any route Once the activation threshold is reason these nerve cells are called all or allows the spread of the drug through the achieved an action potential is initiated. nothing – either an action potential will be whole body. However, despite the fact that The threshold of activation of the nocicep- triggered or not. Pain intensity depends on morphine can inhibit excitation of the tors varies throughout the body, with the how often the action potentials are sensory neuron at the site of an injury, cornea in the eye being a site where the triggered. there is no consensus about whether top- threshold is relatively low compared with In situations where there is tissue ical application of morphine to painful the skin, for example. This means that the injury, less stimulus is required to trigger wounds is an effective and safe therapy degree of stimulus required to trigger pain pain and the pain elicited by that stimulus (Farley, 2011). in the cornea is much lower than the skin. is disproportionately large. This process is Reaching an action potential depends called peripheral sensitisation. It is a result Converting a stimulus into a on the quantity of stimulus – a large stim- of chemicals released in the inflammatory pain signal ulus will cause a reaction in a high number process making the receptors and ion Agonism of receptors on the sensory nerve of receptors, and this will help the cell channels more excitable – more ready to endings leads to excitation of the sensory achieve its threshold more rapidly. A low react. In the cola bottle analogy this would nerve by production of an action potential level stimulus might cause an interaction be like giving the cola bottle a little shake (Fig 2). Nerve signals are conducted along with some receptors and an influx of a before you put the mint in.

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Implications for practice Box 1. glossary Understanding of receptors is increasing all the time and this improves the manage- ● Afferent: travelling from the periphery to the spinal cord (dorsal horn) ment of pain. The TRPV1 receptor responds ● Agonist: a protein key that fits a specific receptor “lock” and causes a reaction to to high temperatures (above 42°C), to acid occur, for example open an ion channel and to the active ingredient of the chilli ● Antagonist: a protein key that fits a specific receptor “lock” and prevents a reaction pepper (capsaicin). The presence of TRPV1 from occurring, for example blocking the ion channel receptors on the mucous membranes is ● Cutaneous: of the skin what makes food containing chilli feel hot. ● Dorsal horn: the route into the spinal cord that (most) sensory nerves take – These are the receptors that make pepper towards the back of the cord spray an extremely effective attack-pre- ● Nerve: a bundle of axons (the long conduction cables of neurons), can include a vention measure, and the reason to avoid number of different types of neurons rubbing the eyes after preparing chillies. ● Neuron: a cell that, when excited by a stimulus, produces an electrical or chemical Repeated activation of TRPV1 receptors signal (often used interchangeably with nerve) can tire them out temporarily so there are ● Neurotransmitters: chemicals that carry signals between one nerve cell and many pain-relieving preparations that another (amino acids or proteins that provide the key to receptor locks) target these receptors including capsaicin ● Nociceptor: a peripheral sensory neuron that can respond to noxious stimuli cream, which is applied to the skin. Once ● Noxious (stimulus): harmful or potentially harmful stimulus – can be immediately the burning sensation has worn off harmful or harmful if left for a relatively long time (for example high temperature or the nociceptor cannot be activated for long-lasting medium-high temperature) a few hours. This has been used to alleviate ● Mechanical stimulus: usually a high pressure distributed over a small surface area neuropathic pain (caused by damage – often another way of saying punctate pressure when talking about or dysfunction of sensory nerves) (Hoper noxious stimuli et al, 2014), and in arthritis (Laslett and ● Punctate pressure: pressure applied to a very small surface area Jones, 2014). ● Primary afferent fibre: a term used for all sensory neurons arriving in the dorsal Prostaglandin is a chemical produced horn but usually meaning those carrying pain signals (A-delta and C fibres) in inflammation that sensitises the local ● Receptor: a protein molecule found on the cell surface that provides the lock for a sensory nerve endings by interaction with specific key a receptor called PGE2. Anti-inflammatory ● Sensitisation: a process that lowers the activation threshold of the nerve either by medication like ibuprofen reduces pain by causing an increase in the number of surface receptors or by opening ion channels inhibiting the production of prosta- ● Stimulus: something that causes a physiological response (single stimulus, glandin, so the nerve endings have a plural stimuli) normal threshold for activation instead of ● Synapse: small space between one nerve cell and another across which an a reduced threshold even when the tissues electrical or chemical signal is passed are damaged. ● Terminal: an ending, usually the end of the sensory nerve in the spinal cord Unfortunately, although anti-inflam- ● Threshold: the lowest stimulus intensity that evokes pain matories are extremely effective in pain ● Visceral: of the (internal) organs reduction, they also have a number of problems associated with their use including gastric irritation and ulceration, The intensity of pain is usually propor- Farley P (2011) Should topical opioid analgesics be regarded as effective and safe when applied to renal dysfunction, increased risk of tional to the intensity of the stimulus. In chronic cutaneous lesions? Journal of Pharmacy thrombus formation, bronchospasm in an injured part of the body the threshold and Pharmacology; 63: 6, 747-756. some people with asthma, and increased for activation of the pain receptors is Hoper J et al (2014) High concentration capsaicin bleeding time (Bruno et al, 2014). The reduced and this increased sensitivity for treatment of peripheral neuropathic pain: effect on somatosensory symptoms and identification of National Institute for Health and Care serves to remind us to protect the injured treatment responders. Current Medical Research & Excellence has produced guidance on when area while healing takes place. Pain recep- Opinion; 30: 4, 565-574. to use them, and how to use them in a tors can be exhausted by using capsaicin, Laslett LL, Jones G (2014) Capsaicin for osteoarthritis pain. Progress in Drug Research; 68: variety of disorders and situations. Gener- while the threshold of activation can be 277-291. ally the advice is to use them in the lowest raised by using morphine or anti-inflam- Marvizon J C et al (2010) Pharmacology of the effective dose for the shortest time (NICE). matory medication. opioid system. In: Beaulieu P et al (eds) Pharmacology of Pain. Seattle WA: International Part two of this series will look at Association for the Study of Pain. Conclusion the movement of the pain signal to the Merksy H, Bogduk N (1994) IASP Taxonomy. Part Acute pain is a sensation caused by acti- spinal cord and the brain and how knowl- III: Pain terms, a current list with definitions and vating pain receptors throughout the body edge of this pathway can help provide notes on usage. In: Merksy H, Bogduk N (eds) Classification of Chronic Pain. Seattle: IASP Press. (except the brain and cartilage) with chem- effective pain relief. NT National Institute for Health and Care Excellence ical, mechanical or thermal stimuli. It (2015) Key Therapeutic Topics: Non-steroidal takes a certain amount of stimulus to set References Anti-inflammatory Drugs. London: NICE. Bear M F et al (2001) The somatic sensory system. nice.org.uk/ktt13 off an action potential, but once the activa- In: Bear M F et al (eds) Neuroscience: Exploring the tion threshold has been reached the pain Brain. Baltimore, MA: Lippincott Williams and For more on this topic go online... signal will be rapidly transmitted to the Wilkins. Bruno A et al (2014) Variability in the response to Evidence on NSAID use in soft spinal cord, and from there to the brain. non-steroidal anti-inflammatory drugs: tissue injuries Once the signal reaches the brain we mechanisms and perspectives. Basic and Clinical Bit.ly/NTNSAIDSoftTissue become aware of the pain. Pharmacology and Toxicology; 114: 1, 56-63.

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