Stimuli

• Nociceptive terminals of primary sensory neurons are stimulated by noxious stimuli 2,4

Impulse Transmission

• Action potentials are generated 2

Sensory Fibers

• Action potentials pass along Ad- and C-type peripheral afferent sensory fibers 2,4

Cord Junctions

• Action potentials arrive at junctions between the peripheral afferent sensory fibers and spinal cord neurons 2,3,4

Dorsal Horn

• Junctions between the peripheral afferent sensory fibers and spinal cord neurons are shown within the dorsal horn 3,4

Synapse

• Arrival of the action potentials causes voltage-gated calcium channels to open in the terminals of the peripheral afferent sensory fibers 1,2

Calcium Release

• Opening of the channels enables the influx of calcium into the peripheral afferent sensory fiber terminals, which causes vesicles containing neurotransmitter molecules to fuse with the pre-synaptic membrane and release their contents into the synaptic cleft 1

Synaptic Cleft

• Neurotransmitter molecules (e.g. glutamate, substance P) diffuse across the synaptic cleft 1,2,3,4
• Neurotransmitters bind to receptors on ion channels in the post-synaptic membrane 1,4

Post Synaptic Cell

• Activation of receptors in the post-synaptic membrane, either via G-protein coupled effector enzymes, or directly via ion channels, enables the efflux of potassium and influx of calcium and sodium into the post-synaptic cell 1,4

Nociceptive Nueron

• The influx of sodium enables the continuation of action potentials from the peripheral afferent sensory fibers, and the transmission of impulses along the axons of the spinal cord neurons to the brain 1,4

Pain Perception

• Information about pain is received and processed by the higher centers in the brain (thalamus, cerebral cortex) and the individual perceives pain 2

Opioid Receptors

• Areas of the spinal cord and brain are shown where the sensations of pain and the affective and psychological aspects of pain are perceived. These include the substantia gelatinosa, periaqueductal gray, reticular formation, parabrachial nucleus, hypothalamus, thalamus, cingulate cortex, and cortex 2, 5,6,7,8.
• Regions of the spinal cord and brain where µ-type opioid receptors are found include the substantia gelatinosa, periaqueductal gray, reticular formation, hypothalamus, thalamus, and cortex 5,6,7,8. These regions show considerable overlap with the regions that enable the perception of pain. Regions where pain is perceived are shown in brown; regions where opioid receptors are found are shown in blue.
• To reduce the level of perceived pain, endogenous opioids (enkephalins, dynorphin) are released by interneurons in the dorsal horn in response to severe/persistent pain. The opioids bind to G proteins associated with µ-type opioid receptors, with the following results:
  • Inhibition of pre-synaptic release of glutamate
  • Increased potassium conductance across the post-synaptic membrane.

  These events prevent the transmission of pain to the higher centers 2,4,5,6

• To combat severe or persistent nociceptive or neuropathic pain, administration of exogenous opioids (e.g. morphine) mimics the effects of endogenous opioids at the µ opioid receptor resulting in blockade of the pain response 2,5.