3.15 Pain Pathways

The primary afferent nociceptors comprise free, unmyelinated nerve endings that are responsive to mechanical, thermal and chemical stimuli. These are relatively, but not completely, specific. Mechanoreceptors and temperature receptors, for example, are nociceptors only above a certain threshold. Following tissue trauma, the release of chemical mediators initiates nociception while activating an inflammatory response

Stimulation of these nociceptive afferents leads to propagation of impulses along the peripheral nerve fibres to the spinal cord by two parallel pathways. The first is via myelinated A-d fibres, of diameter 2–5 mm, and rapidly conducting at between 12 and 30 ms. This type of pain is fast, localized and sharp, and provokes reflex withdrawal responses. The second route to the spinal cord is via non-myelinated C fibres, of smaller diameter (0.4–1.2 mm) and which conduct impulses more slowly at between 0.5 and 2.0 ms C fibres mediate pain sensations that are diffuse and dull.

The primary afferents terminate in the dorsal horn of the spinal cord. The cell bodies lie in the dorsal root ganglia. A-d fibres synapse in the laminae of Rexed I and V, while the C fibres synapse in the substantia gelatinosa. (This comprises lamina II and a part of lamina III.) They relay with various classes of second-order neurons in the cord, some of which are ‘nociceptive-specific’, which respond selectively to noxious stimuli and are located in the superficial laminae, and others of which are ‘wide dynamic range’, are non-specific and are located in the deeper laminae.

Most of the secondary afferents decussate to ascend in the lateral spinothalamic tract, although some pass up the posterolateral part of the cord. These fibres pass through the medulla, midbrain and pons, giving off projection neurons as they do so, before terminating in the ventral posterior and medial nuclei of the thalamus.

From the thalamus there is a specific sensory relay to areas of the contralateral cortex: to somatic sensory area I (SSI) in the post-central gyrus, to somatic sensory area II (SSII) in the wall of the sylvian fissure separating the frontal from the temporal lobes, and to the cingulate gyrus, which is thought to mediate the affective component of pain. The separation between sensory–discriminative and affective areas of the cortex is likely to be an oversimplification.

One of the major complexities of pain pathways is the modulation of afferent impulses which occurs at numerous levels, including the dorsal horn where there is a complex interaction between afferent input fibres, local intrinsic spinal neurons, descending central efferents. Afferent impulses arriving at the dorsal horn themselves initiate inhibitory mechanisms which limit the effect of subsequent impulses. As pain fibres travel rostrally, they also send collateral projections to the higher centres such as the periaqueductal grey (PAG) matter and the locus ceruleus of the midbrain. Descending fibres from the PAG project to the nucleus raphe magnus in the medulla, and to the reticular formation to activate descending inhibitory neurons. These travel in the dorsolateral funiculus to terminate on interneurons in the dorsal horn. . These fibres from the PAG are thought to be the main source of inhibitory control. Descending inhibitory projection also derives from the locus ceruleus. The inhibitory activity mediated from the PAG is also stimulated by endorphins released from the pituitary and which act directly at that site

This represents one aspect of modulation. Synaptic transmission between primary and secondary nociceptive afferents can be ‘gated’ by interneurons. These neurons in the substantia gelatinosa can exert pre-synaptic inhibition on primary afferents, and post-synaptic inhibition on secondary neurons, thereby decreasing the pain response to a nociceptive stimulus. The inhibitory internuncials can be activated by afferents which subserve different sensory modalities, such as pressure (A-b fibres). This phenomenon underlies the use of counter-irritation, dorsal column stimulation, TENS and mechanical stimulation (‘rubbing it better’). Descending central efferents from the PAG and locus ceruleus can also activate these inhibitory interneurons.

these are numerous. Excitatory amino acids such as glutamate and aspartate have a major role in nociceptive transmission at the dorsal horn, where there are NMDA, non-NMDA, kainite, glutamate, AMPA, neurokinin, adenosine, 5-HT, GABA, a-adrenergic receptors, and m, j and d opioid receptors. The primary afferents release various peptides, among them substance P, neurokinin A and calcitonin gene-related peptide (CGRP). There are different neurotransmitters in the various descending inhibitory pathways, which include neuropeptides (enkephalins and endorphins) in the PAG, metenkephalin and 5-HT in the nucleus raphe magnus pathway and noradrenaline in the locus ceruleus descending pathway.

The usual target for analgesics is via ligand–receptor blockade, and the large number of receptor types means that you will only be able to give one or two examples. Opioid receptors, for instance, are expressed in the cell body of the dorsal root ganglion and transported both centrally to the dorsal horn, and peripherally. There are also receptors at higher centres such as the PAG, and so opiates exert their actions at numerous sites in the CNS. Ketamine acts on the open calcium channel of the NMDA receptor, amitriptyline modifies descending noradrenergic pathways, clonidine acts at pre-synaptic and post-synaptic a2-receptors, while NSAIDs predominantly have a peripheral action which attenuates the hyperalgesia associated with the inflammatory response. The future may lie in analgesics that will regulate gene expression and exert selective modification. (Leave this final flourish until the end otherwise your impressed and interested examiner might inconveniently ask for details.)

Stimulus Release of neurotransmitter Trigger a delta or C fibres Primary afferent travels to Dorsal Horn Secondary decussates and travels in spinothalamic tract Travels through medulla MB Pons to Thalamus Tertiary - sensory cortex