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Chapter 8: Pain Modulation and Mechanisms

Nachum Dafny, Ph.D., Department of Neurobiology and Anatomy, The UT Medical School at Houston


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8.1 Pain Modulation

Most, if not all, ailments of the body cause pain. Pain is interpreted and perceived in the brain. Pain is modulated by two primary types of drugs that work on the brain: analgesics and anesthetics. The term analgesic refers to a drug that relieves pain without loss of consciousness. The term central anesthesia refers to a drug that depresses the CNS. It is characterized by the absence of all perception of sensory modalities, including loss of consciousness without loss of vital functions.

Opiate Analgesia (OA)

The most effective clinically used drugs for producing temporary analgesia and relief from pain are the opioid family, which includes morphine, and heroin. There are currently no other effective pain therapeutic alternatives to opiates. Several side effects resulting from opiate use include tolerance and drug dependence (addiction). In general, these drugs modulate the incoming pain information in the spinal and central sites, as well as relieve pain temporarily, and are also known as opiate producing analgesia (OA). Opiate antagonist is a drug that antagonizes the opioid effects, such as naloxone or maltroxone, etc. They are competitive antagonists of opiate receptors. The brain has a neuronal circuit and endogenous substances to modulate pain.

Endogenous Opioids

Opioidergic neurotransmission is found throughout the brain and spinal cord and appears to influence many CNS functions, including nociception, cardiovascular functions, thermoregulation, respiration, neuroendocrine functions, neuroimmune functions, food intake, sexual activity, aggressive locomotor behavior as well as learning and memory. Opioids exert marked effects on mood and motivation and produce euphoria.

Three classes of opioid receptors have been identified: μ-mu, δ-delta and κ-kappa. All three classes are widely distributed in the brain. The genes encoding each one of them have been cloned and found to be members of the G protein receptors. Moreover, three major classes of endogenous opioid peptides that interact with the above opiate receptors have been recognized in the CNS: β-endorphins, enkephalins and the dynorphins. These three opioid peptides are derived from a large protein precursor by three different genes: the proopiomelanocortin (POMC) gene, the proenkephalin gene and the prodynorphin gene. The opioid peptides modulate nociceptive input in two ways: 1) block neurotransmitter release by inhibiting Ca2+ influx into the presynaptic terminal, or 2) open potassium channels, which hyperpolarizes neurons and inhibits spike activity. They act on various receptors in the brain and spinal cord. Enkephalins are considered the putative ligands for the δ receptors, β endorphins for the μ-receptors, and dynorphins for the κ receptors. The various types of opioid receptors are distributed differently within the central and peripheral nervous system. There is evidence for functional differences in these receptors in various structures. This explains why many unwanted side effects occur following opiate treatments. For example, mu (μ) receptors are widespread in the brain stem parabrachial nuclei, a respiratory center and inhibition of these neurons elicits respiratory depression.

Central or peripheral terminals of nociceptive afferent fibers contain opiate receptors where exogenous and endogenous opioids could act to modulate the ability to transmit nociceptive information. Moreover, high densities of opiate receptors are found in periaqueductal gray (PAG), nucleus raphe magnus (NRM), and dorsal raphe (DR) in the rostral ventral medulla, in the spinal cord, caudate nucleus (CN), septal nucleus, hypothalamus, habenula and hippocampus. Additional detailson opiate receptors is provided later in this lecture.

Systemically administered opioids at analgesic doses activate spinal and supraspinal mechanisms via μ, δ, and κ type opioid receptors and modulate pain signals.

8.2 Neuronal Circuits that Modulate Pain

For many years it was suggested that somewhere in the CNS there is a circuit that can modulate incoming pain information. The gate control theory and the ascending/descending pain transmission system are two suggestions of such a circuit.

Gate Control theory

The first pain modulatory mechanism called the "Gate Control" theory was proposed by Melzack and Wall in the mid 1960s. The concept of the gate control theory is that non-painful input closes the gates to painful input, which results in prevention of the pain sensation from traveling to the CNS (i.e., non-noxious input [stimulation] suppresses pain).

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Figure 8.1
The gate control theory of pain modulation. The gate control theory is based on presynaptic inhibition of pain information produced by mechanical stimulation, and provides the basic rationale for the TENS.

The theory suggests that collaterals of the large sensory fibers carrying cutaneous sensory input activate inhibitory interneurons, which inhibit (modulate) pain transmission information carried by the pain fibers. Non-noxious input suppresses pain, or sensory input “closes the gate” to noxious input (Figure 8.1). The gate theory predicts that at the spinal cord level, non-noxious stimulation will produce presynaptic inhibition on dorsal root nociceptor fibers that synapse on nociceptors spinal neurons (T), and this presynaptic inhibition will block incoming noxious information from reaching the CNS (i.e., will close the gate to incoming noxious information).

The gate theory was the rationale for the idea behind the production and the use of transcutaneous electrical nerve stimulation (TENS) for pain relief. To be effective, the TENS unit produces two different current frequencies below the pain threshold that can be tolerated by the patient. This procedure has partial success in pain therapy.

Stimulation produced analgesia (SPA)

Evidence for an intrinsic analgesia system was demonstrated by intracranial electrical stimulation of certain discrete brain sites. These areas are the periaqueductal gray (PAG) and nucleus raphe magnus (NRM), dorsal raphe (DR), caudate nucleus (CN), septal nucleus (Spt) and other nuclei. Such stimulation inhibits pain, (i.e., producing analgesia without behavioral suppression), while the touch, pressure and temperature sensation remain intact. SPA is more pronounced and lasts a longer time after stimulation in humans than in experimental animals. Moreover, during SPA, the subjects still respond to nonpainful stimuli such as touch and temperature within the circumscribed area of analgesia. The most effective CNS sites for SPA are the PAG and the raphe nuclei (RN).

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Figure 8.2
Periaqueductal gray and raphe nucleus stimulation produces analgesia.

Electrical stimulation of PAG or NRM inhibits spinal thalamic cells, (i.e. spinal neurons that project monosynaptically to the thalamus) in laminae I, II and V so that the noxious information from the nociceptors are modulated at the spinal cord level. PAG has neuronal connections to NRM.

The action of the PAG most likely occurs by activation of the descending pathway from NRM and probably also by activation of ascending connections acting on higher subcortical levels of the CNS. Moreover, electrical stimulation of PAG or NRM produces behavioral analgesia, (i.e., stimulation produced analgesia, see Figure 8.2). Stimulation produced analgesia (SPA) elicits release of endorphin and is blocked by the opiate antagonist naloxone.

During PAG and/or RN stimulation, serotonin (5-HT) is also released from ascending and descending axons in subcortical nuclei, in spinal trigeminal nuclei and in the spinal cord. This release of 5-HT modulates pain transmission by inhibiting incoming sensory activity. Depletion of 5-HT by electrical lesion of the raphe nuclei or by a neurotoxic lesion produced by local injection of a chemical agent like parachlorophenylalanine (PCPA) results in blocking the ability of both opiate (intracranial and systemic) and electrical stimulation to produce analgesia.

Stimulation Produced Analgesia (SPA) (continued)

To verify whether the electrical stimulation produced analgesia via the release of opiate and serotonin, the area was locally microinjected with morphine or 5-HT. These microinjections indeed produce analgesia (Figure 8.3). These procedures also provide a method of identifying brain regions associated with pain suppression and help to produce a map of pain centers. The most effective method of producing opiate analgesia (OA) is by intracerebral injection of morphine into the PAG.

The PAG and RN and other brain structures where analgesia is produced are also rich in opiate receptors. Intracerebral opioid administration produced analgesia and SPA can be blocked by either systemic or by local microinjections of naloxone, the morphine antagonist, into the PAG or RN. Therefore, it has been suggested that the two (OA and SPA) operate by a common mechanism.

If OA and SPA act through the same intrinsic system, then the hypothesis that opiates activate a pain-suppression mechanism is more likely. In fact, present evidence indicates that microinjections of an opiate into the PAG activate an efferent brainstem system that suppresses pain transmission at segmental (spinal cord) levels (See Figure 8.3). These observations indicate that analgesia elicited from the PAG requires a descending pathway to the spinal cord.

8.3 Pain Mechanisms

Ascending and Descending Pain Suppression Mechanism

The primary ascending pain fibers (the A δ and C fibers) reach the dorsal horn of the spinal cord from peripheral sites to innervate the nociceptor neurons in Rexed laminae I & II. Cells from Rexed lamina II make synaptic connections in Rexed layers IV to VII. Cells, especially in laminae I and VII of the dorsal horn, give rise to ascending spinothalamic tracts. At the spinal level, opiate receptors are located at the presynaptic ends of the nocineurons and at the interneural level layers IV to VII in the dorsal horn. Activation of opiate receptors at the interneuronal level produces hyperpolarization of the neurons, which result in the inhibition of firing and the release of substance P, a neurotransmitter involved in pain transmission, thereby blocking pain transmission. The circuit that consists of the periaqueductal gray (PAG) matter in the upper brain stem, the locus coeruleus (LC), the nucleus raphe magnus (NRM) and the nucleus reticularis gigantocellularis (Rgc) contributes to the descending pain suppression pathway, which inhibits incoming pain information at the spinal cord level.

As mentioned previously, opioids interact with the opiate receptors at different CNS levels. These opiate receptors are the normal target sites for neurotransmitters and endogenous opiates such as the endorphins and enkephalins. As a result of binding at the receptor in subcortical sites, secondary changes which lead to a change in the electrophysiological properties of these neurons and modulation of the ascending pain information.

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Figure 8.3A
Periaqueductal gray and raphe nucleus electrical stimulation produces analgesia.

 

 

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Figure 8.3B
Microiontophoretical administration of morphine in the periaqueductal gray and 5-HT in the Raphe nucleus produces analgesia.

What activates the PAG to exert its effects? It was found that noxious stimulation excites neurons in the nucleus reticularis gigantocellularis (RGC). The nucleus Rgc innervates both the PAG and NRM. The PAG sends axons to NRM, and neurons in NRM send their axons to the spinal cord. Moreover, bilateral dorsolateral funiculus (DLF) lesions (DLFX) block the analgesia produced by both electrical stimulation and by microinjection of opiates directly into the PAG and NRM, but they only attenuate the systemic analgesic effects of opiates (Figure 8.4). These observations support the hypothesis that discrete descending pathways in the DLF are necessary for both OA and SPA.

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Figure 8.4
Dissection of the DLF (X) blocks the analgesic effects produced by both electrical stimulation and by microinjection of opioid and 5-HT directly into the PAG and NRM respectively.

The DLF is comprised of fibers originating from several brainstem nuclei, which are serotonergic (5-HT) from neurons located within the nucleus raphe magnus (NRM); dopaminergic neurons originating from ventral tegmental area (VTA) and adrenergic neurons originating from the locus coeruleus (LC). These descending fibers suppress noxious input at the nociceptive spinal cord neurons in laminae I, II, and V.

Opiate receptors have also been found in the dorsal horn of the spinal cord, mainly in Rexed laminae I, II, and V, and these spinal opiate receptors mediate inhibitory effects on dorsal horn neurons transmitting nociceptive information. The action of morphine appears to be exerted both in the spinal cord and brainstem nuclei (i.e., PAG and NRM). Systemic morphine acts on both brain stem and spinal cord opiate receptors to produce analgesia. Morphine binds the brainstem opiate receptors, which activates the brainstem descending serotonergic pathway to spinal cord (i.e., the DLF), and they have an opioid-mediated synapse at the level of the spinal cord.

This observation suggests that noxious stimuli (rather than non-noxious stimulus - see Gate Theory) are critical for activation of the descending pain modulation circuit (i.e., pain suppresses pain via the descending DLF pathway).

In addition, there are ascending connections from the PAG and raphe nuclei to PF-CM complex. These thalamic areas are part of the ascending pain modulation at the diencephalon level.

Stress-Induced Analgesia (SIA)

Analgesia may be produced in certain stressful situations. Exposure to a variety of painful or stressful events produces an analgesic reaction. This phenomenon is called stress induced analgesia (SIA). SIA has been thought to provide insight into the psychological and physiological factors that activate endogenous pain control and opiate systems. For example, soldiers wounded in battle or athletes injured in sports events sometimes report that they do not feel pain during the battle or game; however, they will experience the pain later after the battle or game has ended. It has been demonstrated (in animals) that electrical shocks cause stress-induced analgesia. Based on these experiments, it is assumed that the stress the soldiers and the athletes experienced suppressed the pain which they would later experience.

It has been suggested that endogenous opiates are released in response to stress and inhibit pain by activating the midbrain descending system. Moreover, some SIA exhibited cross tolerance with opiate analgesia, which indicates that this SIA is mediated via opiate receptors. Experiments using different parameters of electrical shock stimulation demonstrate that such stress produces analgesia and some of these stresses that produce analgesia could be blocked by the opioid antagonist naloxone, whereas others were not blocked by naloxone. These observations lead to the conclusion that both opiate and non-opiate forms of SIA exist.

8.4 Summary

The modulation of pain by electrical brain stimulation results from the activation of descending inhibitory fibers, which modulate (block) the input and output of laminae I, II, V and VII neurons. The route from the PAG to the spinal cord is not direct. It appears to involve a link with the 5-HT-rich raphe nuclei, as well as norepinephrine (NE) from the locus coeruleus (LC) and dopamine (DA) from the ventral tegmental area (VTA). Axons from the raphe nuclei, locus coeruleus and VTA project to the spinal cord dorsal horn by way of the DLF to terminate in lamina I, II and IV to VII (i.e., stimulation of NRM, VTA and LC inhibits the neuronal activity of lamina I, II and IV to VII neurons).

Opioid and serotonergic antagonists reverse both local opiate analgesia and brain-stimulation produced analgesia. This suggests that OA and SPA are produced via the same descending inhibitory system.

In conclusion, in the CNS, much of the information from the nociceptive afferent fibers results from excitatory discharges of multireceptive neurons. The pain information in the CNS is controlled by ascending and descending inhibitory systems, using endogenous opioids, or other endogenous substances like serotonin as inhibitory mediators. In addition, a powerful inhibition of pain-related information occurs in the spinal cord. These inhibitory systems can be activated by brain stimulation, intracerebral microinjection of morphine, and peripheral nerve stimulation. Centrally acting analgesic drugs activate these inhibitory control systems. However, pain is a complex perception that is influenced also by prior experience and by the context within which the noxious stimulus occurs. This sensation is also influenced by emotional state. Therefore, the response to pain varies from subject to subject.

Test Your Knowledge

  • Question 1
  • A
  • B
  • C
  • D
  • E

According to the descending pain suppression theory,

A. Descending spinothalamic fibers produce presynaptic inhibition of Rexed lamina VII neurons.

B. Pain stimuli activate descending fibers in the dorsolateral fasciculus.

C. Mechanical stimulation produces descending postsynaptic inhibition of Rexed lamina VIII neurons.

D. Transection of the dorsal column blocks the descending fibers producing analgesia.

E. Descending corticospinal fibers produce postsynaptic inhibition of nociceptive spinal neurons will not affect pain sensation.

According to the descending pain suppression theory,

A. Descending spinothalamic fibers produce presynaptic inhibition of Rexed lamina VII neurons. This answer is INCORRECT.

The spinothalamic fibers are ascending fibers that carry pain information to the thalamus. The descending dorsolateral fasciculus fibers suppress pain in the spinal cord.

B. Pain stimuli activate descending fibers in the dorsolateral fasciculus.

C. Mechanical stimulation produces descending postsynaptic inhibition of Rexed lamina VIII neurons.

D. Transection of the dorsal column blocks the descending fibers producing analgesia.

E. Descending corticospinal fibers produce postsynaptic inhibition of nociceptive spinal neurons will not affect pain sensation.

According to the descending pain suppression theory,

A. Descending spinothalamic fibers produce presynaptic inhibition of Rexed lamina VII neurons.

B. Pain stimuli activate descending fibers in the dorsolateral fasciculus. This answer is CORRECT!

C. Mechanical stimulation produces descending postsynaptic inhibition of Rexed lamina VIII neurons.

D. Transection of the dorsal column blocks the descending fibers producing analgesia.

E. Descending corticospinal fibers produce postsynaptic inhibition of nociceptive spinal neurons will not affect pain sensation.

According to the descending pain suppression theory,

A. Descending spinothalamic fibers produce presynaptic inhibition of Rexed lamina VII neurons.

B. Pain stimuli activate descending fibers in the dorsolateral fasciculus.

C. Mechanical stimulation produces descending postsynaptic inhibition of Rexed lamina VIII neurons. This answer is INCORRECT.

Mechanical stimulation produces presynaptic inhibition, not postsynaptic inhibition.

D. Transection of the dorsal column blocks the descending fibers producing analgesia.

E. Descending corticospinal fibers produce postsynaptic inhibition of nociceptive spinal neurons will not affect pain sensation.

According to the descending pain suppression theory,

A. Descending spinothalamic fibers produce presynaptic inhibition of Rexed lamina VII neurons.

B. Pain stimuli activate descending fibers in the dorsolateral fasciculus.

C. Mechanical stimulation produces descending postsynaptic inhibition of Rexed lamina VIII neurons.

D. Transection of the dorsal column blocks the descending fibers producing analgesia. This answer is INCORRECT.

The dorsal column does not carry the descending dorsolateral fiber, therefore their transaction will not affect SPH.

E. Descending corticospinal fibers produce postsynaptic inhibition of nociceptive spinal neurons will not affect pain sensation.

According to the descending pain suppression theory,

A. Descending spinothalamic fibers produce presynaptic inhibition of Rexed lamina VII neurons.

B. Pain stimuli activate descending fibers in the dorsolateral fasciculus.

C. Mechanical stimulation produces descending postsynaptic inhibition of Rexed lamina VIII neurons.

D. Transection of the dorsal column blocks the descending fibers producing analgesia.

E. Descending corticospinal fibers produce postsynaptic inhibition of nociceptive spinal neurons will not affect pain sensation. This answer is INCORRECT.

Corticospinal fibers innervate motor neurons, and have no effect on nociceptive spinal neurons.

 

 

 

 

 

 

 

 

 

  • Question 2
  • A
  • B
  • C
  • D
  • E

The Melzack-Wall gate theory refers to:

A. Ascending pain suppression system.

B. Non-noxious input suppresses pain at the spinal cord.

C. Electrical simulation-produced analgesia.

D. Cortical control system suppresses pain.

E. Descending pain suppression system.

The Melzack-Wall gate theory refers to:

A. Ascending pain suppression system. This answer is INCORRECT.

B. Non-noxious input suppresses pain at the spinal cord.

C. Electrical simulation-produced analgesia.

D. Cortical control system suppresses pain.

E. Descending pain suppression system.

The Melzack-Wall gate theory refers to:

A. Ascending pain suppression system.

B. Non-noxious input suppresses pain at the spinal cord. This answer is CORRECT!

Melzack and Wall assume that peripheral non-noxious stimulation will inhibit presynaptically the pain conducting pulses at the spinal cord target cells (T cells) and will prevent pain sensation from being transmitted to higher centers.

C. Electrical simulation-produced analgesia.

D. Cortical control system suppresses pain.

E. Descending pain suppression system.

The Melzack-Wall gate theory refers to:

A. Ascending pain suppression system.

B. Non-noxious input suppresses pain at the spinal cord.

C. Electrical simulation-produced analgesia. This answer is INCORRECT.

D. Cortical control system suppresses pain.

E. Descending pain suppression system.

The Melzack-Wall gate theory refers to:

A. Ascending pain suppression system.

B. Non-noxious input suppresses pain at the spinal cord.

C. Electrical simulation-produced analgesia.

D. Cortical control system suppresses pain. This answer is INCORRECT.

E. Descending pain suppression system.

The Melzack-Wall gate theory refers to:

A. Ascending pain suppression system.

B. Non-noxious input suppresses pain at the spinal cord.

C. Electrical simulation-produced analgesia.

D. Cortical control system suppresses pain.

E. Descending pain suppression system. This answer is INCORRECT.

 

 

 

 

 

 

 

 

  • Question 3
  • A
  • B
  • C
  • D
  • E

Electrical stimulation in the periaqueductal gray elicits:

A. Circular movement

B. Analgesia

C. Catatonia

D. Tremors

E. Hyperactivity

Electrical stimulation in the periaqueductal gray elicits:

A. Circular movement This answer is INCORRECT.

B. Analgesia

C. Catatonia

D. Tremors

E. Hyperactivity

Electrical stimulation in the periaqueductal gray elicits:

A. Circular movement

B. Analgesia This answer is CORRECT!

PAG stimulation causes the release of endorphins to the circulation which produce analgesia.

C. Catatonia

D. Tremors

E. Hyperactivity

Electrical stimulation in the periaqueductal gray elicits:

A. Circular movement

B. Analgesia

C. Catatonia This answer is INCORRECT.

D. Tremors

E. Hyperactivity

Electrical stimulation in the periaqueductal gray elicits:

A. Circular movement

B. Analgesia

C. Catatonia

D. Tremors This answer is INCORRECT.

E. Hyperactivity

Electrical stimulation in the periaqueductal gray elicits:

A. Circular movement

B. Analgesia

C. Catatonia

D. Tremors

E. Hyperactivity This answer is INCORRECT.

 

 

 

 

 

 

 

 

  • Question 4
  • A
  • B
  • C
  • D
  • E

The following nuclei are involved in the serotonergic descending modulation system of pain:

A. Locus coeruleus

B. Central gray

C. Ventral trigeminal area

D. Raphe nuclei

E. Ventro-posterior medial thalamus

The following nuclei are involved in the serotonergic descending modulation system of pain:

A. Locus coeruleus This answer is INCORRECT.

B. Central gray

C. Ventral trigeminal area

D. Raphe nuclei

E. Ventro-posterior medial thalamus

The following nuclei are involved in the serotonergic descending modulation system of pain:

A. Locus coeruleus

B. Central gray This answer is INCORRECT.

C. Ventral trigeminal area

D. Raphe nuclei

E. Ventro-posterior medial thalamus

The following nuclei are involved in the serotonergic descending modulation system of pain:

A. Locus coeruleus

B. Central gray

C. Ventral trigeminal area This answer is INCORRECT.

D. Raphe nuclei

E. Ventro-posterior medial thalamus

The following nuclei are involved in the serotonergic descending modulation system of pain:

A. Locus coeruleus

B. Central gray

C. Ventral trigeminal area

D. Raphe nuclei This answer is CORRECT!

Stimulation at the central gray and the Raphe nuclei produces analgesia via dorsolateral funiculus descendign fibers.

E. Ventro-posterior medial thalamus

The following nuclei are involved in the serotonergic descending modulation system of pain:

A. Locus coeruleus

B. Central gray

C. Ventral trigeminal area

D. Raphe nuclei

E. Ventro-posterior medial thalamus This answer is INCORRECT.

 

 

 

 

 

 

 

 

 

 

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