Ascending & Descending Pain Modulation Pathways

Pain modulation is the process of alteration of nociception along its transmission pathway.
Painful stimulus is detected by nociceptors in the peripheral, the two nociceptors that detect
painful stimulus are A delta (detect pain that is described as ‘first pain’, which is sharp and does
not last for long) and C fibres (detect pain that is described as ‘second pain’, which is dull and
longer lasting). Signals travel from the nociceptors to the dorsal horn of the spinal cord to
synapse with second order neurons, mostly in the substantia gelatinosa and the marginal zone of
the spinal cord. From the spinal cord, 2nd order neurons cross over and travel via the
spinothalamic tract to higher areas of the brain where conscious sensation of pain is perceived.

The pathway can be modulated by ascending or descending neural pathways. A mechanism

called gate theory of pain is a type of ascending modulation, the theory suggests how blunting of
painful stimulus can be achieved via activating a non-painful sensation. Whereby
mechanoreceptors, which are responsible for fine touch signalling, act as a ‘gate’ by decreasing
pain signals in nociceptors. A beta fibres (mechanoreceptors) send excitatory collaterals to
inhibitory enkephalinergic interneurons, this causes the interneurons to release enkephalin which
binds to opioid receptors on the presynaptic (nociceptor) and postsynaptic (2nd order neuron of
nociception) neuron. Enkephalin binding will cause inhibition of calcium ion influx in the
presynaptic neuron therefore no glutamate or substance P is released, and will cause opening of
potassium channels in the postsynaptic neuron therefore hyperpolarizing the cell. These two
effects dampen nociceptive signals from reaching higher areas in the brain, thus reducing pain
perception. Pain is still felt as nociceptors have an inhibiting effect on the enkephalinergic
interneurons thus some pain signals are still propagated along the nociceptive pathway. This
mechanism explains why rubbing an injured area (thus increasing firing in the A beta fibres)
reduces pain perception.

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Modulation can also occur via interactions with descending projections from the brainstem. The
cingulate, insula, amygdala and hypothalamus activate the periaqueductal grey in the brainstem,
which subsequently activates further descending pathways from the parabrachial nucleus, locus
coeruleus, reticular formation and raphe nuclei. These structures interact with the second order
neuron and the nociceptor in various ways. The descending inhibitory input from the locus
coeruleus releases noradrenaline and may synapse with either the nociceptor or the second order
neuron, inhibiting the activity of the either one. Descending excitatory input from the raphe
nuclei release serotonin to local enkephalinergic interneurons, that themselves inhibit the axonal
end of the presynaptic nociceptor, via enkephalin binding to opioid receptors with inhibit
calcium ion influx therefore inhibiting neurotransmitter release. The end result in a dampening of
perception of pain due to less action potentials being generated within the dorsal horn.