Pain Systems I: Nociceptors And Nociceptive Pathways
Pain is defined as an unpleasant sensory or emotional experience associated with actual or potential tissue damage. Much of what is known about pain mechanisms has derived from animal-based research where the affective component is unclear. For this reason neuroscientists prefer to use the term nociception, which defines the processing of information about damaging stimuli up to the point where perception occurs. This is an important distinction because tissue damage is not inevitably linked to pain and vice versa.
Nociceptors are found in the skin, visceral organs, skeletal and cardiac muscle and in association with blood vessels. They conduct information about noxious events to the dorsal horn of the spinal cord where the primary afferents synapse.
There are basically two types of nociceptor, distinguished by the diameter of the afferent fibre and the stimulus required to activate it.
• The high-threshold mechanoreceptor (HTM) is activated by intense mechanical stimulation and innervated by thinly myeli- nated Aδ fibres conducting at 5–30 m/s.
• Polymodal nociceptors (PMN) respond to intense mechanical stimulation, temperatures in excess of about 42 °C and irritant chemicals. These receptors are innervated by unmyelinated C fibres conducting at 0.5–2 m/s.
Sharply localized pain is thought to be conducted in the faster conducting fibres whereas poorly localized pain is conducted in the C fibres.
Although nociceptors are histologically simple free nerve endings, the process of transduction at the receptor ending is complex and is associated with some of the chemical mediators of inflammation and tissue damage. Thus, adenosine triphosphate (ATP), bradykinin, histamine and prostaglandins all either activate or sensitize the receptor ending. Indeed, some of the transmitters in the nociceptive pathway are themselves released peripherally (e.g. substance P) to produce further sensitization of the receptor ending. Nociceptor receptor sensitization helps explain the perception of heightened pain (primary hyperalgesia) in areas of tissue damage and is essentially a peripheral phenomenon usually of relatively short duration.
Chronic and referred pain
Pain that lasts many months is known as chronic pain. It is often disabling and resistant to treatment. It may arise following damage to either the peripheral or central nervous system or chronic inflammatory states (e.g. osteoarthritis). Changes in peripheral nociceptor sensitivity does not explain secondary hyperalgesia, in which light touch outside the immediate area of cutaneous damage can lead to pain.
A more serious problem associated with peripheral or central nerve damage is allodynia. In this condition light stroking of the skin can give rise to severe pain. Disturbed patterns of sensory input to the dorsal horn (e.g. following compression or sectioning of a peripheral nerve trunk) can lead to long-term changes in the processing of noxious information in the dorsal horn. At these sites, the arrival of axonally conducted substance P in the superficial layers of the dorsal horn leads to both an increase in receptive field sizes and the sensitivity of some dorsal horn neurones. These functional changes are mediated in part by the synaptic release of glutamate acting on postsynaptic N-methyl-D-aspartate (NMDA) receptors and may contribute to some chronic pain states.
In addition, allodynia and secondary hyperalgesia are linked to increased activity in microglia and astrocytes, and the release of a number of agents (interleukin-1 and -6, tumour necrosis factor [TNF], nitric oxide [NO], ATP and prostaglandins).
Damage to peripheral nerve trunks can lead to complex regional pain syndrome (CPRS). One form is associated with disturbances to the sympathetic nervous system (SNS) (CRPS-1, of which reflex sympathetic dystrophy is an example). Severing a peripheral nerve trunk leads to the formation of a neuroma which acts as a genera- tor of ectopic action potentials (ectopic foci) sending barrages of action potentials to the spinal cord. This activity is thought to explain the development of phantom limb pain with the neuroma being sensitive to both mechanical stimulation and SNS activity (i.e. noradrenaline).
Visceral nociceptors project into the spinal cord via the small-diameter myelinated and unmyelinated fibres of the autonomic nervous system (ANS), and synapse at the spinal level of their embryological origin. The development of pain in an internal organ can therefore produce the perception of a painful stimulus in the skin rather than the organ itself, at least in the early stages of inflammation – a phenomenon known as referred pain. For example, inflammation of the appendix initially leads to pain being perceived at the umbilicus.
The majority of nociceptors and thermos receptors project into the spinal cord via the dorsal root, although some pass through the ventral horn. On reaching the spinal cord these sensory nerves synapse in a complex fashion in the dorsal horn.
• The postsynaptic cell conveying nociceptive information projects up the spinal cord as the spinothalamic, spinoreticulothalamic and spinomesencephalic tracts (latter not shown on figure), with the axons crossing at the spinal level by passing around the central canal of the cord. This crossing of fibres often occurs a few levels above where the nociceptive fibres enter the cord, and thus damage in the region of the central canal as seen in syringomyelia results in a loss of pain and temperature sensibility (see Chapter 54).
• The postsynaptic cell and presynaptic nociceptive nerve terminal receive synapses from other peripherally projecting somatosensory systems, descending projections from the brainstem and interneurones intrinsic to the dorsal horn. Many of these interneurones contain endogenous opioid substances known as enkephalins and endorphins which activate opioid receptors of which there are three main subtypes (μ, κ, δ). There is therefore enormous potential for modifying the transfer of nociceptive information at the level of the dorsal horn (see Chapter 33).
• The ascending nociceptive pathways synapse in a number of different central nervous system (CNS) sites. Information concerning noxious events ascends in either the spinothalamic tract (providing accurate localization) or the spinoreticulothalamic system (transmit- ting information concerning the affective components of pain). However, some of the nuclei in the brainstem to which these path- ways project (e.g. the raphé nucleus and locus coeruleus) in turn send axons back down the spinal cord to the dorsal horn, and can be exploited in the control of chronic pain syndromes (see Chapter 33).
• The thalamic termination of the spinothalamic pathway is in the ventroposterior and intralaminar nuclei (IL) (including the posterior group), which in turn project to multiple cortical areas but especially the primary and secondary somatosensory area (SmI and SmII) and the anterior cingulate cortex. Lesions to any of these sites alter the perception of pain but do not produce a true and complete loss of pain or analgesia, and indeed may even produce a chronic pain syndrome. Such syndromes are not uncommonly seen with small thalamic cerebrovascular accidents.
The thermoreceptors, and to a lesser extent the nociceptors, also project to the hypothalamus, which has an important role in thermoregulation and the autonomic response to a painful stimulus (see Chapters 3 and 11).