Pain Pathways

• Nociceptors are free, typically unmyelinated nerve endings that are abundant in skin and musculoskeletal tissue
• They may be activated by noxious stimuli which are:
• Exogenous e.g. capsaicin
• Endogenous i.e. mediators released by tissue damage: bradykinin, histamine, serotonin, ACh, H⁺ and K⁺
• Activation causes Na⁺/Ca²⁺ influx, depolarisation and initiation of an action potential

Activation and sensitisation of nociceptors

• Some mediators sensitise nociceptors by reducing their threshold for activation:
• Substance P, prostaglandins, leukotrienes, neurokinin A and CGRP
• Neighbouring nociceptors are sensitised, producing a zone of primary hyperalgesia around the injury
• Low-intensity stimuli may now produce pain, with increased sensitivity to thermal stimuli

• The action potential travels along Aδ and C fibres, whose cell bodies lie in the dorsal root ganglion, to the dorsal horn of the spinal cord
• At the pre-synaptic terminal, Ca²⁺ influx causes release of excitatory neurotransmitters:
• Glutamate: acting at AMPA, kainate and NMDA receptors
• Aspartate: acting at NMDA receptors
• Substance P: acting at NK-1 receptors

• First order neurones synapse with second order neurones in Rexed's laminae of the dorsal horn
• Two types of second order neurone exist:
1. Nociceptive-specific neurones: respond only to noxious stimuli; found in the superficial laminae
2. Wide dynamic range neurones: respond to both noxious and non-noxious stimuli; found in the deeper laminae (IV and V)

• Repeated C fibre input removes the Mg²⁺ block of the NMDA receptor, increasing the sensitivity of dorsal horn neurones
• This underlies the medium- and long-term changes seen in chronic pain states:
• Wind-up: a progressive increase in dorsal horn neurone response to repeated stimuli, greater than would be expected from a linear stimulus-response relationship
• Central sensitisation: low-intensity stimuli produce pain, with a zone of secondary hyperalgesia in uninjured tissue
• NB unlike peripheral sensitisation, there is no increased response to thermal stimuli
• Long-term potentiation and altered gene expression

• Most second order neurones decussate and ascend in the anterolateral system
• Tracts are somatotopically organised; fibres from caudal segments lie laterally and those from rostral segments medially


• Spinothalamic tract
• Lateral (pain and temperature) and anterior (crude touch) divisions
• Fast, discriminative fibres project directly to the ventral posterior nucleus of the thalamus
• Slow, affective fibres synapse in the reticular formation and intralaminar thalamic nuclei, then project to the hypothalamus, limbic system and autonomic centres
• Spinoreticular tract: terminates in the reticular formation; arousal, motor and autonomic reflexes
• Spinomesencephalic tract: terminates in the PAG; integration of pain responses and autonomic reflexes


• For comparison, touch, vibration and proprioception (Aβ) ascend ipsilaterally in the dorsal columns before decussating in the medulla to form the medial lemniscus

• In parallel, a protective polysynaptic withdrawal reflex occurs at spinal cord level, before the stimulus is perceived

• GABA
• Endogenous opioids e.g. enkephalins acting at MOP receptors
• Opioid receptors are pre-synaptic G_i protein-coupled receptors
• Following tissue damage, they are synthesised in the dorsal root ganglion and transported peripherally along the sensory nerve, forming a peripheral mechanism of analgesia

• Transmission at the dorsal horn is influenced by other afferent inputs, as described by the gate control theory

• Act as negative feedback, opposing the positive feedback of peripheral and central sensitisation
• Descend in the dorsolateral funiculus


• Periaqueductal grey (PAG)
• Midbrain area projecting to the nucleus raphe magnus (NRM) in the medulla, which in turn projects to the dorsal horn
• Serotonergic (5-HT)
• Locus coeruleus (LC)
• Brainstem nucleus projecting to the dorsal horn
• Noradrenergic (α₂-adrenoceptors)


• Both pathways activate inhibitory enkephalinergic interneurones in the substantia gelatinosa, reducing onward transmission

• Second order neurones synapse with third order neurones in the ventral posterior and intralaminar nuclei of the thalamus
• Third order neurones project to:
• Primary somatosensory cortex (postcentral gyrus of the parietal lobe): location and intensity of pain
• Anterior cingulate and frontal cortex: emotional aspects of pain
• Limbic system, hypothalamus and autonomic centres: affect, memory and autonomic responses
• Perception is therefore shaped by mood, expectation and prior experience, which is the basis of the biopsychosocial model of pain