Pain control

Pain modulation (modification) in the CNS

• Certain mechanisms in the CNS modulate pain sensation by either exaggerating or suppressing it.
• The former is almost always pathological (e.g., in the thalamic syndrome) while the latter is mostly a physiologic process.
• Pain suppression was explained by the gate theory but recently it was produced through a special "pain control analgesia
system".

Pain is transmitted by 2 parallel systems to the cortex

• Two types of neurons that transmit pain signals along the anterolateral pathway:
o Neospinothalamic tract:
▪ Aδ fibers that transmit acute pain
o Paleospinothalamic tract:
▪ C fibers that transmit
▪ mostly slow chronic pain

Pain control is mediated by:

1. Gate theory
2. Analgesia system
3. Brain opiate system

Gate theory of pain Inhibition

o This theory assumes that the various sites of relay in the pathway of pain act as gates that can be opened or
closed.
o The main gate is located at the dorsal horns in the SGR substantia gelatinosa of Rolandi (= spinal gate).
o Other gates, are located at the thalamus as well as in the reticular formation.
o At the spinal gate, pain transmission can be blocked (i.e., the gate is closed) by
1. Collaterals from the thick myelinated A-beta fibers in dorsal column
2. Descending fibers from certain higher center (corticofugal fibers).
o Such block occurs mainly through presynaptic inhibition. The gate theory explains the relief of pain achieved by
counter irritants (e.g. liniments and mustard plaster), skin rubbing or shaking of the painful
part.
o These methods stimulate mechanoreceptors, which activate the neurons in the dorsal column
resulting in relief of pain
o A mustard plaster is a poultice of mustard seed powder spread inside a protective dressing
and applied to the body to stimulate healing.
o It can be used to warm muscle tissues and for chronic aches and pains.
o It was once part of conventional medical treatment, and available in prepared versions in
pharmacies.
o It fell from favor in the 20th century and is now used only as a home remedy
o SGR:
▪ Acts as gate (through which pain impulses reach lateral spino-thalamic tract)
▪ It can be closed by impulses from:
1. A beta fibers; So Rubbing of skin
2. A delta fibers, So Aquipuncture
3. Corticofugal fibers; So Thinking
• All these fibers cause pre-synaptic inhibition of pain fibers by activation an interneuron which
secrete GABA
Pain control Analgesic Pathway
o Analgesic pathway that interferes with pain transmission is often
considered as descending pain pathway
o The descending axons end at lower brainstem and spinal levels
interneurons and inhibit synaptic transmission between the afferent
nociceptor neurons and the secondary ascending neurons.
o Some of the neurons in these inhibitory pathways release morphine like
endogenous opioids. These opioids inhibit the propagation of input
through the higher levels of the pain system.
o This is a specific system that blocks pain transmission in the the CNS
o Its major constituents include the following:
1. The periventricular nuclei in the hypothalamus.
2. The periaqueductal gray area (PAG) in the midbrain and upper
pons(enkephalin).
3. The raphe magnus nucleus (RMN) in the lower pons and upper
medulla (serotonin).
4. A pain inhibitory complex (PIC) in the dorsal horn of the spinal
cord (enkephalin).
o Certain cortical areas are also involved in the pain analgesia system
(specially the limbic association areas). and the principal mediators in this
System are the opioid peptides

Analgesia system of the brain and spinal cord (corticofugal signals)

• Descending pathway from cortex to centers in the brain stem and then to
spinal dorsal horn neurons can suppress transmission of both fast and slow
pain
• Neurotransmitters that suppress pain are: enkephalins, endorphins &
serotonin
• They cause both pre-synaptic and post-synaptic inhibition

Mechanism of pain control by the analgesia system

o The analgesia system produces its effects by stimulating the PIC.
o The PIC consists of short enkephalinergic neurons that terminate on the central endings of pain-conducting
afferent nerves.
o The released enkephalin binds to the opiate receptors present on these nerve endings and prevent the release
of the pain transmitters (presynaptic inhibition).
o Pain inhibition by this mechanism occurs through the following pathways:
A. Peripheral pathway of pain inhibition (spinal inhibition)
• Collaterals from the thick A-beta nerve fibers that transmit mechanoreceptive
• sensations directly stimulate the PIC.
• This explains how pain is relieved by counter-irritants, mechanical stimuli (e.g., skin rubbing)
and acupuncture.
• Depending on such mechanism, severe pain can be relieved by electrical stimulation of thick
sensory nerve fibers.
 B. Central pathway of pain inhibition (= supraspinal inhibition)
• Excitation of the hypothalamic periventricular nuclei or Certain Cortical areas) depresses pain
as follows
1. The nerve fibers from the hypothalamic or the cortical areas release beta-endorphins
which stimulates the PAG.
2. The PAG projects enkephalinergic neurons (i.e., neurons which Release enkephalins)
that stimulate the raphe magnus nucleus (RMN).
3. The Raphi magnus nucleus projects serotonergic neurons (i.e., neurons which release
serotonin) that block pain signals through activating the PIC.
• Analgesia system can inhibit pain transmission at the thalamic intralaminar nuclei and the
reticular nuclei in the brain.

Brain Opiate System

• These are morphine-like neurotransmitters that are naturally formed in the body (so they are called the own body's
morphine).
• Morphine (the active substance in opium) is a potent analgesic substance that produces its effect by binding to specific
opiate receptors in the nervous system.
• Similarly, the opioid peptides are analgesic substances that act by binding to the opiate receptors.
• The most important opioid peptide include the following:
o Enkephalins
o β Endorphin
o Dynorphin
• Endogenous opioid peptides [Types]:
1. β Endorphins
▪ 30 amino acids
▪ Present in:
1. Hypothalamus
2. Pituitary
▪ They are secreted in stress conditions (e.g., battle) → reaching opioid receptors in body causing
analgesia (stress analgesia). They are stronger than enkephalins
▪ Endorphins in hypothalamus act as: Neurotransmitters
▪ Endorphins in pituitary act as: Neurohormone
2. Enkephalins:
▪ Met & leu enkephalins are:
▪ Pentapeptides (5 amino acids)
▪ They are derived from pro-enkephalin
▪ They are present in different parts of CNS eg:
1. Periaqueductal grey matter
2. SGR “Substania Gelatinosa of Rolandi”
3. Limbic system
▪ They are degraded by 2 types of enzymes; enkephalinase enzymes (A and B).
3. Dynorphin:
▪ They are stronger than enkephalins
▪ They are:
• 17 amino acids
• Very potent analgesic
• Responsible for addiction & tolerance for opiates
• Opiate receptors:
o There are 5 types and are mainly present in the analgesia system and the central endings of the pain
conducting fibers at the dorsal roots
o They can be stimulated both exogenously (by morphine) and endogenously (by the opioid peptides).
o Types:
▪ μ Receptor (Mu):
• Have high affinity to Endorphins
▪ δ Receptor (Delta):
• Have high affinity to Enkephalins
▪ K Receptor (Kappa):
• Have high affinity to Dynorphin
o Sites:
▪ Periaqueductal gray area
▪ Raphe magnus nucleus: In medulla
o Blocked by: Naloxone (Which used for their identification)
Stress analgesia
• Certain stress conditions are associated with analgesia e.g. during the stress of
the battle, severely-wounded soldiers frequently feel no pain till the battle is
over.
• Such analgesia is produced by impulses discharged from the cerebral cortex and
hypothalamus, which excite the central pathway of pain inhibition
• Stress-induced analgesia (SIA) refers to a reduced pain response after stress
exposure, which is mediated by descending pain-inhibitory circuits and may be
an indicator of adequate centrally mediated pain control.
• These studies have revealed that individual sensitivity to stress-induced
analgesia can vary greatly and that this sensitivity is coupled to many different
phenotypes including the degree of opioid sensitivity and immediate response.
• Furthermore, stress-induced analgesia is influenced by age, gender, and prior
experience to stressful, painful, or other environmental stimuli.
• there are key roles for the endogenous opioid, monoamine, cannabinoid, γ-
aminobutyric acid and glutamate systems.

Acupuncture
• Acupuncture relieves pain by both activating the peripheral pathway of pain inhibition as well as
by psychogenic excitation of the central pathway.
• Both mechanisms lead to stimulation of the PIC in the dorsal horns of the spinal cord, which blocks
pain transmission by releasing enkephalins
• For this reason, the efficiency of acupuncture is increased by enkephalinase-inhibitor drugs and is
decreased by morphine antagonist drugs (e.g. naloxone) which block the opiate receptors.