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Pain modulation

Created: 19/6/2004
Updated: 21/7/2021

The transmission of information from primary afferents to secondary neurons in the CNS is subject to “gating” (modulation). Nociceptive sensory information is gated in the substantia gelatinosa of the spinal cord. Gating is of two kinds:

1. Local – segmental antinociception
2. Widespread – supraspinal antinociception which utilises descending pathways from the brainstem.

The Gate Control Theory was devised by Patrick Wall and Ronald Melzack in 1965. This theory states that pain is a function of the balance between the information travelling into the spinal cord through large nerve fibres and information travelling into the spinal cord through small nerve fibres. If the relative amount of activity is greater in large nerve fibres, there should be little or no pain. However, if there is more activity in small nerve fibres, then there will be pain.
Figure 5: Original gate control theory represented schematically

The Gate Theory of Pain

Gate control theory

This neuronal circuitry is present in the posterior roots of the spinal cord: Ab and C fibres coming from the skin, for example, stimulate the neuron N implicated in nociception, but this stimulation cannot occur when the peripheral stimulus is weak because enkephalinergic interneurons (E) stimulated by  sensory  somesthetic  fibres  Ab  inhibit nociceptive transmission. It is only when the stimulus is strong that the nociceptor C fibres lower the efficacy of this inhibitory control. According to the theory, lamina II inhibitory interneurons can be activated directly or indirectly (via excitatory interneurons) by stimulation of non-noxious large sensory afferents from the skin that would then block the projection neuron and therefore block the pain. Thus rubbing a painful area relieves the pain.

TENS – trans-electrical nerve stimulators

Devices commonly used by physiotherapists (or during labour) to stimulate the large (Ab) sensory fibres in peripheral nerves, in the hope that they will in turn activate the inhibitory neurons of lamina II and block pain transmission. Importantly, these devices work best when placed on/near the skin of the injured/painful region. They use high frequency, low intensity stimuli to activate the low threshold fibres. They are ineffective if they are positioned far away from the painful site. In practice, most counter-stimulation techniques require the use of “near noxious” stimulation intensities (felt as a buzzing, or tingling sensation), which recruit both Ab and Ad afferents, to be maximally effective. From the spinal cord, the messages go directly to several places in the brain, including the thalamus, midbrain and reticular formation. It may be that Ad fibres rather than Ab fibres are best at exciting lamina II inhibitory interneurones because the Ad fibres are able to recruit the help of the supraspinal control systems.
Some brain regions that receive nociceptive information are involved in perception and emotion. Also, some areas of the brain connect back to the spinal cord - these connections can change or modify information that is coming into the brain. This is one way that the brain can reduce pain, by a mechanism known as supraspinal (descending) analgesia. It uses feedback loops that involve several different nuclei in the brainstem reticular formation. Two important areas of the brainstem that are involved in reducing pain are the periaqueductal gray (PAG) and the nucleus raphe magnus (NRM).

The PAG is important in the control of pain. This region surrounds the cerebral aqueduct in the midbrain. Stimulation of parts of the PAG produces more pronounced analgesia than stimulation of either the NRM or the locus coeruleus (LC). Neurosurgeons can implant electrical stimulating electrodes near the PAG of intractable (chronic) pain patients so that a small electrical shock can be delivered through a device. This is wired so that the patient can control the level of self-stimulation and hence level of analgesia. This is known as stimulus-induced analgesia. The PAG contains enkephalin-rich neurons that excite the NRM and/or LC neurons by disinhibiting GABAergic interneurons in the PAG. This allows PAG (anti-nociceptor) neurons to excite the amine-containing cells in the NRM and LC that in turn project down to the spinal cord to block pain transmission by dorsal horn cells by different mechanisms:

1. Direct postsynaptic inhibition of projection cells causing hyperpolarisation of the membrane potential due to activation of G protein-linked receptors that cause the opening of potassium channels.

2. Presynaptic inhibition of neurotransmitter release from primary afferent terminals. This works by activating G protein-linked receptors that cause closing of calcium channels, thus reducing transmitter release.

A second descending system of serotonin-containing neurons exists.  The cell bodies of these neurons are located in the raphe nuclei (NRM) of the medulla and, like the noradrenaline-containing neurons, the axons synapse on cells in lamina II.  They also synapse on cells in lamina III.  Stimulation of the raphe nuclei produces a powerful analgesia and it is thought that the serotonin released by this stimulation activates the inhibitory interneurons even more powerfully than the noradrenaline and thus blocks pain transmission.  However, serotonin may not be specifically involved in inhibition of pain transmission.  Serotonergic agonists do not have significant analgesic effects.  Serotonin neurons appear to inhibit all somatosensory transmission, and may have a function in the initiation of sleep.  A complicating factor is that serotonin receptors are found in many places in the dorsal horn, including on primary afferents from C fibres.  Serotonin may act to presynaptically inhibit pain by blocking C fibre terminals.  C fibres release not just the excitatory amino acid glutamate but also a peptide known as “substance P”.  Substance P is a neuromodulator, like most peptides.  Although it can alone activate lamina I neurons, it seems mainly to amplify the effect of the glutamate that is released.  Substance P and glutamate appear to be co-released from C fibres, but the proportions of each may vary.

Some of the interneurons of lamina II contain enkephalins.  Enkephalins have been shown pharmacologically to bind to the same receptors as opiate drugs like morphine and heroin.  Therefore, it seems likely that opiate drugs may act by mimicking the activity of the interneurones of lamina II.  It has not yet been fully established how endogenous enkephalins work at the spinal level.  They may act as ‘trophic factors’, somehow amplifying the response of the post-synaptic dendrites to the action of GABA.  Enkephalin-containing neurons have also been found in the medulla, mid-brain and hypothalamus.  (People probably become addicted to opiates because of their effects at these mid-brain and hypothalamic sites).


Transcutaneous electrical nerve stimulation does not relieve labour pain: updated systematic review.
Carroll D, Moore RA, Tramèr MR, McQuay HJ.
Contemporary Reviews in Obstetrics and Gynecology 1997; Sept:195-205.

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