What are the pathways involved in the sensation of pain and how can we

manipulate them for our benefit

March 2003: Describe the pathways involved in pain perception and its treatment.

March 2004: Describe the pathways responsible for the modulation of painful stimuli in
the central nervous system.

March 2005: Describe the neural mechanisms and pathways involved in nociception.
How is nociception modulated?
Introduction
Pain is often useful in alerting us to tissue damage and triggering appropriate
motor responses to minimize further bodily harm. NAME THE DISEASE WHERE
PAIN DOESN’T OCCUR AND DEMONSTRATE HOW USEFUL PAIN IS
However, pain that is unrelated to tissue injury, such as the persistence of pain after
healing of injury, is harmful and debilitating. In fact, chronic pain is a major medical
health problem that causes enormous emotional suffering and financial costs to patients
and their carers. Fortunately, advances in our understanding of how pain is modulated
physiologically have led to effective pain control techniques. There is a huge variability
in the way nociception leads to pain responses as the sensation of pain is modulated by
behavioural experiences. Nociception refers to the physiological process by which
noxious stimuli are detected by specialized transducers (nociceptors) and transmitted to
the central nervous system. Pain is defined as the subjective response of the individual to
the nociceptive input to the brain and may be unrelated to the actual physical parameters
of intensity and duration of the stimulus. Not all noxious stimuli cause pain to be felt and
conversely pain can occur in the absence of nociception, e.g. phantom pain. In 1965,
Wall & Melzack proposed the ‘gate control theory’ to explain how inhibitory
interneurons in lamina II of the dorsal horn (substantia gelatinosa) induce analgesia by
inhibiting spinothalamic tract transimission neurons in response to non-nociceptive
afferent inputs and descending inhibitory pathways. Analgesia can then be induced
clinically by fitting stimulating electrodes into the periventricular gray region or by
administering opiates to activate descending pain modulating pathways.

In 1906, Sherrington proposed that nociceptors, primary sensory neurons

activated by stimuli capable of causing tissue damage, are the first step in nociception.
The existence of nociceptors has since been confirmed by electrophysiological studies
which show that certain primary sensory neurons are activated by harmful stimuli
(noxious heat, pressure and chemicals) but not by innocuous stimuli (warming and light
touch). One major way by which noxious stimuli are transduced into electrical impulses
in nociceptive afferent fibres is believed to be via vanilloid receptor 1 (VR1). This
receptor is a typical ligand-gated cation channel, particularly permeable to Na+ and Ca+,
which opens in response to capsaicin-like compounds, temperatures above 45oC and high
[H+] (pH<5.5). Capsaicin is a potent agonist for VR1 and produces a Ca2+ influx large
enough to cause nerve terminal degeneration. This property of capsaicin allows it to be
used clinically as topical ointments to relieve the pain of peripheral neuropathy such as
post-herpetic neuralgia caused by shingles. The opening of VR1 is facilitated when
bradykinin is produced in response to tissue injury. Bradykinin acts by binding to G-
protein coupled receptors and following activation of protein kinase C, bradykinin leads
to phosphorylation of VR1 which facilitate its opening. Bradykinin receptor antagonists
would cause analgesia but unfortunately no such drug is available for clinical use yet.
Prostaglandins are synthesized during inflammation and tissue ischaemia, and they also
sensitize nociceptive nerve terminals by inhibiting K+ channels and facilitating the
opening of cation channels. Fortunately, we can block the sensitization of nociceptors by
prostaglandins by administering non-steroidal anti-inflammatory drugs (NSAIDS), such
as aspirin, which inhibit arachidonate cyclooxygenase and thus inhibit prostaglandin and
thromboxane synthesis. NSAIDS provide effective pain relief for a variety of conditions
such as arthritis, muscular pain, toothache, dysmenorrhoea, and are used in combination
with opioids for posteroperative pain. EVIDENCE THAT NSAIDS HAVE A CENTRAL
EFFECT VIA ACTION IN SPINAL CORD? Nociceptive transducers other than VR1
include acid-sensitive cation channels and P2X3 receptors which are activated by H+ and
ATP respectively, both of which are released during tissue injury.

The two main types of nociceptive afferent fibres are small diameter, thinly
myelinated Aδ fibres and unmyelinated C fibres. Aδ fibres detect noxious thermal and
mechanical stimuli causing sharp, well-localised pain whereas C fibres are polymodal
(activated by high intensity mechanical, chemical, hot or cold stimuli) and cause dull
burning pain.

These nociceptive afferent fibres, with their cell bodies in the dorsal root ganglia,
enter the dorsolateral tract of Lissauer and give off branches that terminate in laminae I,
II and V of the dorsal horn.

DIAGRAM OF DORSAL HORN, LECTURE NOTE OR P.563 RANG AND DALE.

P.388 KANDEL AND SWARTZ

Projection neurons in the dorsal horn relay nociceptive inputs to higher centers in
the brain via five major ascending pathways. The main ascending pathway is the
spinothalamic tract which arises from neurons in laminae I and V-VII. It decussates to
ascend in the contralateral anterolateral white matter region and terminates in the ventral
and posterior nuclei of the thalamus. The axons of nociceptive neurons in laminae VII
and VIII ascend via the spinoreticular tract and may be ipsilateral or contralateral.
Nociceptive neurons in laminae I and V form the spinomesencephalic tract which project
to the mesencephalic reticular formation. Neurons in laminae III and IV that are activated
by noxious stimuli project through the spinocervical tract to the lateral cervical nucleus.
Neurons from this nucleus then decussate and project through the medial lemniscus to
midbrain nuclei and to the ventroposterior lateral and posterior medial nuclei of the
thalamus. The last ascending pathway is the dorsal column of the spinal cord which
conveys information from nociceptive neurons in laminae III and IV to the cuneate and
gracile nuclei in the medulla. The thalamic nuclei that receive nociceptive information
project to different regions of the somatosensory cortex which suggest there are several
pathways that process nociceptive information in the cortex.

The transmission of nociceptive information from nociceptors to the central

nervous system can be modulated at different points along these pathways. These
physiological mechanisms of regulating nociceptive transmission play an important role
in reducing sensitivity to pain during emergency situations to allow more useful
responses for survival purposes. In 1965, Wall & Melzack proposed the ‘gate control
theory’ which explains how nociceptive transmission in the dorsal horn is modulated by
the interaction between afferent nerve fibres, inhibitory interneurons and projection
neurons.

Fig 27-8 ON P.392 IN KANDEL AND SWARTZ

 The gate control theory provided the basis of our understanding of pain
modulation and allowed us to draw predictions that led to effective pain treatments, e.g.
transcutaneous stimulation of myelinated dorsal column fibres induced analgesia by
suppressing projection neuron activity. In addition to the gate control theory, descending
inhibitory pathways also regulate impulse transmission in the dorsal horn. The existence
of descending inhibitory controls was first discovered when Reynolds in 1969 found that
electrical stimulation of the periaqueductal grey (PAG) area of the midbrain in rats
induced profound analgesia by inhibiting nociceptive neurons in the spinal cord. It is now
known that stimulation of neurons in the PAG and nucleus reticularis
paragigantocellularis (NRPG) leads to activation of serotonergic nucleus raphe magnus
(NRM) neurons in the rostroventral medulla. Neurons from NRM project via the
dorsolateral funiculus to the substantia gelatinosa of the dorsal horn where they release 5-
hydroxytrptamine and enkephalin. Another descending inhibitory control pathway is
formed by noradrenergic neurons from the locus ceruleus, which lies in the caudal
midbrain and rostral pons, which release noradrenaline in the dorsal horn.

p.566 Rang and Dale diagram of descending control system

DIAGRAM TO SHOW HOW 5-HT EKEPHALIN, NA CAUSE INHIBITION?

By understanding the neurotransmitters involved in the descending inhibitory pain

control pathways, we can induce analgesia pharmacologically for clinical purposes by
activating these same pathways. In 1975, Hughes and Kosterlitz discovered that the
central nervous system contains endogenous opioid peptides, β-endorphin, met-
enkephalin, leu-enkephalin and dynorphin. The superficial dorsal horn contains many
inhibitory interneurons which exert presynaptic and postsynaptic inhibitory actions at
primary afferent synapses by employing enkephalin and endorphin as neurotransmitters.
These opioid peptides act by binding to opiate peptide receptors of which there are three
major classes: μ, δ and κ. We can induce analgesia clinically by administering opiate
receptor agonists such as morphine, one of the most powerful analgesic drug used
clinically.

SLOBBO DIAGRAM OF CELLULAR ACTIONS OF OPIOID RECEPTORS FROM

P.576 IN RANG AND DALE . SEE ALSO P.397 IN KANDEL AND SWARTZ
Or p. 396 of kandel morphine inhibits inhibitory interneuron -> disinhibition of
descending pathways

Topics not covered by essay -> Notes:

Variability of pain perception:
• Variability of pain perception. Hyperalgesia=increased amount of pain in
response to mild noxious stimuli. Allodynia= pain evoked by non-noxious
stimuli. Arise from sensitization of peripheral nociceptive nerve terminals and
 central facilitation of transmission at the level of the dorsal horn and thalamus via
bradykinin and prostaglandins actions on nerve terminals. In dorsal horn,
facilitation blocked by NMDA receptor antagonists and antagonists of substance
P and by inhibitors of NO synthesis. Substance P produce slow depolarising
response and enhance NMDA-receptor-mediated transmission. This leads to
calcium influx and NO synthesis. NO facilitate transmission by mechanisms yet
to be elucidated. Nerve growth factor, produced during inflammation, affect
nociceptive afferent neurons, increasing electrical excitability, chemosensitivity ,
peptide content, and formation of synaptic contacts. NGF increase expression of
genes encoding neuropeptide precursors, receptors and channels thus facilitate
transmission at first synaptic relay in dorsal horn.
• Referred pain = pain arise from viscereal nociceptors but pain felt on skin.
Myocardial infarction leads to pain in left arm. Alden Spencer and Michael
Seltzer first showed that visceral and cutaneous nocieptors converge on same
projection neuron thus possible mechanism of referred pain.
• Transmitters in the pain pathway. A delta and C fibres release glutamate which
act on AMPA receptors. Responsible for fast synaptic transmission at first
synapse in dorsal horn. Slower NMDA receptor mediated response is important in
relation to wind-up phenomenon. Nociceptive afferents also elicit slow excitatory
postsynaptic potentials through release of neuropeptides, especially substance P.
Application of substance P to dorsal horn neurons evokes slow synaptic potentials
that mimic those produced by high-intensity stimulation of primary afferents.
Substance P discovered in 1931 by von Euler & Gaddum. More about tachykinins
(substance P and neurokinin A) on p.571 in Rang and Dale if keen!
• For conclusion, see p.583 Rang & Dale for new approaches.