Mod VI: Pain Pathway

Question 1

_{Pain Pathway}

Two mechanism:

Answer 1

Excitatory Mechanisms = Ascending pathway

Inhibitory Mechanisms – Descending pathway

Question 2

_{Pain Pathway}

Excitatory Mechanisms = Ascending pathway

Answer 2

Physiological pain is mediated by a sensory system consisting of primary afferent neurons, spinal interneurons, ascending tracts, and supraspinal areas

Trigeminal and dorsal root ganglia (DRG) give rise to high-threshold Aδ– and C-fibers innervating peripheral tissues (skin, muscles, joints, viscera)

These specialized primary afferent neurons (nociceptors) transduce noxious stimuli into action potentials and conduct them to the dorsal horn of the spinal cord

When peripheral tissue is damaged, primary afferent neurons are sensitized and/or directly activated by thermal, mechanical, and/or chemical stimuli

Impulses are transmitted to spinal neurons, brainstem, thalamus, and cortex

Repeated nociceptor stimulation can sensitize peripheral and central neurons (activity-dependent plasticity, or “wind-up”)

This can be sustained by changes in the expression of genes coding for various neuropeptides, transmitters, ion channels, receptors, and signaling molecules (transcription-dependent plasticity) in peripheral and central neurons (Baron, Hans, & Dickenson, 2013; Basbaum et al., 2009)

Both induction and maintenance of central sensitization are critically dependent on the peripheral drive by nociceptors, indicating that therapeutic interventions targeting such neurons may be particularly effective, even in chronic pain syndromes (Baron et al., 2013; Richards & McMahon, 2013).

Question 3

_{Pain Pathway}

Inhibitory Mechanisms – Descending pathway

Answer 3

Concurrent with such excitatory events, powerful endogenous mechanisms counteracting pain unfold

This was initially proposed in the “gate control theory of pain” of 1965 and has since been corroborated and expanded by experimental data in the central nervous system (CNS) and in the periphery

In 1990, a “peripheral gate” was discovered at the source of pain generation by demonstrating that immune cell–derived opioid peptides can block the excitation of nociceptors carrying opioid receptors within injured tissue (Figure 1) (Stein et al., 1990)

This represented the first example of many subsequently described neuro-immune interactions relevant to pain (Machelska, 2011; Stein, 1995; Stein & Machelska, 2011)

In the spinal cord, pain inhibition is mediated by the release of opioid peptides, gamma-amino-butyric acid (GABA), or glycine

During ongoing nociceptive stimulation, spinal interneurons upregulate gene expression and production of opioid peptides (Herz, Millan, & Stein, 1989)

Powerful descending inhibitory pathways from the brainstem also become active by operating through noradrenergic, serotonergic, and opioid systems (Basbaum et al., 2009; Schumacher, Basbaum, & Naidu, 2015)

The supraspinal integration of signals from excitatory and inhibitory neurotransmitters, and cognitive, emotional, and environmental factors eventually results in the central perception of pain

Question 4

_{Terminologies - Acute and Chronic Pain - Basic Concepts}

Pain may be divided into two broad categories:

Answer 4

Physiological & Pathological pain

Physiological=acute

Pathological=chronic

Question 5

_{Terminologies - Acute and Chronic Pain - Basic Concepts}

Physiological pain = acute pain

Answer 5

Nociceptive pain is a warning sign that usually elicits reflex withdrawal and thereby protects from further injury

=> POSTOPERATIVE PAIN

Question 6

_{Terminologies - Acute and Chronic Pain - Basic Concepts}

Pathological pain = chronic pain

Answer 6

Neuropathic pain is an expression of the maladaptive operation of the nervous system

It is “pain” as a disease

Question 7

_{Terminologies - Acute and Chronic Pain - Basic Concepts}

Non-malignant chronic pain is frequently classified into

Answer 7

Inflammatory (e.g., arthritic)

Musculoskeletal (e.g., low back pain), headaches

Neuropathic pain (e.g., post-herpetic neuralgia, phantom pain, complex regional pain syndrome, diabetic neuropathy, HIV neuropathy)

Question 8

_{Terminologies - Acute and Chronic Pain - Basic Concepts}

Malignant pain is related to

Answer 8

Cancer and its treatment

Cancer pain can originate from the invasion of the tumor into tissues innervated by primary afferent neurons (e.g., pleura, peritoneum) or directly into peripheral nerve plexus

In the latter case, neuropathic symptoms may be predominant

Could turn into neuropathic pain

Question 9

_{Acute and Chronic Pain - Clinical Concepts: Definitions and Prevalence}

“an unpleasant sensory and emotional experience associated with actual or potential tissue damage” is the definition of:

Answer 9

Pain

^{<strong>[</strong>The International Association for the Study of Pain (IASP)]}

Pain is always a psychological state, even though it often has a proximate physical cause

Question 10

_{Acute and Chronic Pain - Clinical Concepts: Definitions and Prevalence}

The neurophysiological activity in peripheral sensory neurons (nociceptors) and higher nociceptive pathways is

Answer 10

Nociception

is defined as the “neural process of encoding noxious stimuli.”

Nociception is not synonymous with pain

Pain is always a psychological state, even though it often has a proximate physical cause

Question 11

_{Acute and Chronic Pain - Clinical Concepts: Definitions and Prevalence}

When the intricate balance between biological (neuronal), psychological (e.g., learning, memory, distraction), and social (e.g., attention, reward) factors becomes disturbed, what type of pain develops?

Answer 11

Chronic pain

Chronic pain has enormous socioeconomic costs due to health care, disability compensation, lost workdays, and related expenses.

According to a report in 2011, by the Institute of Medicine titled: Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research, pain is a significant public health problem that costs society at least $560-$635 billion annually, an amount equal to about $2,000.00 for everyone living in the U.S.

This includes the total incremental cost of health care due to pain from ranging between $261 to $300 billion and $297-$336 billion due to lost productivity (based on days of work missed, hours of work lost, and lower wages)

Question 12

_{Acute and Chronic Pain - Clinical Concepts: Definitions and Prevalence}

Today, pain’s impact on society is still great, and indeed what are the number one reason patients seek medical advice

Answer 12

Pain complaints

^{(http://pharmacistsalternative.com/uncategorized/pain-part-1/)}

Question 13

_{Acute and Chronic Pain - Bio-psycho-social Concept}

Both cancer and non-cancer patients with chronic pain have in common the complex influences of which factors?

Answer 13

Biological (tissue damage)

Cognitive (memory, expectations)

Emotional (anxiety, depression)

Environmental factors (reinforcement, conditioning)

Question 14

_{Acute and Chronic Pain - Bio-psycho-social Concept}

Pain behaviors such as limping, medication intake, or avoidance of activity are all subject to operant conditioning; that is, they respond to

Answer 14

Reward and punishment

For example, pain behaviors may be positively reinforced by attention from a spouse or healthcare provider (e.g., by inadequate use of medications)

Conversely, such behaviors can be extinguished when they are disregarded or when incremental activity is reinforced by social attention and praise

The interplay between biological, psychological, and social factors results in the persistence of pain and illness behaviors

Besides possible long-term neuronal sensitization, this concept helps us understand why chronic pain may exist without obvious physical cause.

Question 15

_{Acute and Chronic Pain - Pain Management}

The treatment of both acute (e.g., postoperative) and chronic pain remains a major challenge in clinical medicine and public health

One component of pain therapy is the use of analgesic drugs - How do these drugs work?

Answer 15

They interfere with the generation or transmission of impulses in the periphery or CNS meaning nociception

Question 16

_{Acute and Chronic Pain - Pain Management}

Drugs currently used in clinical pain treatment include

Answer 16

Opioids

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Serotonergic compounds

Antiepileptics, and

Antidepressants

Question 17

_{Acute and Chronic Pain - Pain Management}

In chronic pain, treating only nociception is obviously insufficient - why?

Answer 17

A bio-psycho-social approach addresses physical, psychological, and social skills and underscores the patients’ active responsibility to regain control over their life by improving their function and well-being

Question 18

_{Acute and Chronic Pain}

Types of pain include:

Answer 18

• Nociceptive Pain
• Somatic Nociceptive Pain
• Visceral Nociceptive Pain
• Referred Visceral Pain
• Hyperalgesia
• Allodynia
• Neuropathic Pain
• Hyperesthesia

Question 19

_{Types of Pain}

Painful stimulus that causes an organism to adopt protective behaviors that promote healing - Pain with a well defined onset associated with tissue injury from surgery, trauma, or disease related injury including inflammation - These characteristics of which type of pain?

Answer 19

Nociceptive pain

Question 20

_{Types of Pain}

What are the phases of Nociceptive pain?

Answer 20

Transduction

Transmission

Perception

Modulation

Question 21

_{Types of Pain}

Pain that is often described as well-localized sharp, crushing, tearing pain that usually follows a dermatomal pattern

Answer 21

Somatic nociceptive pain

Question 22

_{Types of Pain}

Pain that is poorly localized dull, cramping, or colicky pain associated with peritoneal irritation, dilation of smooth muscle or a tubular passage

Answer 22

Visceral nociceptive pain

Question 23

_{Types of Pain}

Pain that radiates in a somatic dermatomal pattern. Example MI

Answer 23

Referred visceral pain

Question 24

_{Types of Pain​}

Which physiologic change results from prolonged hyper-stimulation which can cause structural and functional changes to both peripheral and central neurons

Answer 24

HyperalgesiaThese changes can cause central sensitization leading to the development neuropathic pain

Question 25

_{Types of Pain​}

Normally, nociceptor terminals have a high activation threshold

They requiring intense stimulation to generate an Ascending pathway

For example, thermal nociceptors are only activated by temperature extremes (>45°C or < 5°C)

However, nociceptors can be made more sensitive to stimuli

Injury to neurons and surrounding tissues expose neighboring nociceptors to irritating substances, including: neurotransmitters, ATP, prostanoids, bradykinin, serotonin, histamine, and hydrogen ions (acid pH), etc.

These substances lower the nociceptor’s activation threshold (sensitize), creating a condition of

Answer 25

Hyperesthesia

Hyperesthesia is a term that encompasses both

allodynia and hyperalgesia

A common example of allodynia is the painful response to touch in an area of a 1st degree burn, e.g. sunburn

Normally, allodynia subsides as healing progresses

Often you will hear Allodynia in association with Multiple Sclerosis

Question 26

_{Types of Pain​}

Hyperesthesia is a term that encompasses both

Answer 26

Allodynia & Hyperalgesia

Question 27

_{Types of Pain​​}

the painful response to touch in an area of a 1st degree burn, e.g. sunburn is a common example of:

Answer 27

Allodynia

Normally, allodynia subsides as healing progresses

Often you will hear Allodynia in association with Multiple Sclerosis

Question 28

_Opioids

Exogenous opioids like hydromorphone, morphine and oxycodone produce analgesia by

Answer 28

mimicking endogenous endorphins

Question 29

_Opioids

Opioids are able to activate which endorphin receptors?

Answer 29

Mu, Kappa & Delta

Question 30

_Opioids

Which opioid receptors are responsible for most of the analgesic effect of opioids and are present on neurons in the spinal cord, brainstem and midbrain?

Answer 30

Mu receptors

Question 31

_Opioids

The opioid receptor family contains three pharmacologically distinct receptors, named

Answer 31

Mu-, delta-, and kappa

(MOR, DOR, KOR)

Question 32

_Opioids

Which type of receptors are Opioid receptors (OR)?

Answer 32

Opioid receptors (OR) are G protein–coupled receptors (GPCR) that are the physiological targets of endogenous opioid peptides

Question 33

_Opioids

Endomorphins and endogenous morphine and exogenous opioids like morphine, fentanyl, oxycodone show selectivity for which receptors elicit analgesia and other effects?

Answer 33

Mu receptors

Question 34

_Opioids

What’s the MOA of Full agonist opioids? What are examples of Full agonist opioids?

Answer 34

Activate the opioid receptors in the brain fully resulting in the full opioid effect

Examples of full agonists are heroin, oxycodone, methadone, hydrocodone, morphine, opium and others

Question 35

_Opioids

What’s the MOA of opioid antagonists? What are examples of opioid antagonists?

Answer 35

An antagonist is a drug that blocks opioids by attaching to the opioid receptors without activating them

Antagonists cause no opioid effect and block full agonist opioids

Examples are naltrexone and naloxone

Naloxone is sometimes used to reverse a heroin overdose

Question 36

_Opioids

Buprenorphine is classified as:

Answer 36

Partial agonist at mu and kappa opioid receptors and as an antagonist at delta receptors.

Buprenorphine is a derivative of the opioid alkaloid thebaine that is a more potent (25 - 40 times) and longer lasting analgesic than morphine

It acts as a partial agonist at mu and kappa opioid receptors and as an antagonist at delta receptors

Question 37

_Opioids

Nubain is classified as:

Answer 37

kappa agonist and partial mu and delta antagonist

(see in OB)

Question 38

_{Pain Pathway}

Most of us in our lifetime may have done something that lead to a painful situation occurring in our bodies - Whether it’s an injury, surgery, illness or disease an uncomfortable sensation may be experienced and potentially perceived as pain - The sensations of pain: pricking, burning, aching, stinging and soreness are the most distinctive of all the sensory modalities - While pain can serve as a warning for protection against further harm, however unmanaged it can also lead to severe and relentless suffering - Pain is manifested by autonomic, psychological and behavioral reactions - The clinical word for pain perception is:

Answer 38

Nociception

Question 39

_{Pain Pathway​}

The body recognizes pain when some sort of stimulus causes a signal to be sent through the nervous system and into the brain

The stimulus can be for instance,

Answer 39

mechanical, such as a puncture from a needle,

chemical, like a burn or a chemical irritation or

thermal

Question 40

_{Pain Pathway​}

Pain stimuli are transformed into […], which are then conducted to the central nervous system.

Answer 40

electrical signals

Question 41

_{Pain Pathway​}

[—] are slow, thin, myelinated fibers associated with sharp/pricking, well localized pain.

Answer 41

A-delta fibers (Að)

Question 42

_{Pain Pathway​}

[—] are very slow, thin, unmyelinated fibers that are associated with a dull, aching, throbbing, diffuse pain.

Answer 42

C fibers

Question 43

_{Pain Pathway​}

There have been three types of nociceptors identified [—], which are free nerve endings

Answer 43

Aδ, Aβ, C-fibers (primary afferent fibers)

Question 44

_{Pain Pathway​}

Which fibers carry electrical signals towards the central nervous system?

Answer 44

Afferent fibers

Question 45

_{Pain Pathway​}

Highly myelinated and of large diameter fibers, therefore allowing for rapid signal conduction. They have a low activation threshold and usually respond to light touch and transmit non-noxious stimuli.

Answer 45

Aβ fibers

Question 46

_{Pain Pathway​}

Lightly myelinated and smaller diameter fibers, and hence conduct more slowly. They respond to mechanical and thermal stimuli. They carry rapid, sharp, pricking pain and are responsible for the initial reflex response to acute pain

Answer 46

Aδ fibers

Question 47

_{Pain Pathway​}

Unmyelinated and are also the smallest type of primary afferent fibers. Hence they demonstrate the slowest conduction. Are polymodal, meaning they respond to chemical, mechanical and thermal stimuli. Activation leads to slow, burning, long lasting pain.

Answer 47

C-fibers

Question 48

_{Pain Pathway​}

THE MAJOR INHIBITORY NEUROTRANSMITTER IN THE NERVOUS

SYSTEM is:

Answer 48

GABA

Aminobutyric acid (GABA) is the major neurotransmitter for fast

inhibitory synaptic transmission

The GABA-A receptor is a chloride channel regulated by GABA binding, and it is now grouped in the superfamily of ligand-gated ion channel receptors, mediated by a G-protein–coupled receptor that increases potassium conductance

Question 49

_{Pain Pathway​}

What’s the major neurotransmitter for fast excitatory synaptic transmission?

Answer 49

Glutamatel-Glutamic acid (glutamate) is the major neurotransmitter for fast excitatory synaptic transmission

Excitatory neurotransmitters are Glutamate and substance P

Question 50

_{Pain Pathway​}

is a secondary rapid inhibitory neurotransmitter, especially in the spinal cord (1,2).

Answer 50

Glycine

Glycine is a secondary rapid inhibitory neurotransmitter, especially in the spinal cord (1,2).

Question 51

_{Pain Pathway​}

Modulators of the GABA-A receptor

Answer 51

Volatile anesthetics and alcohols (87), as well as intravenous agents such as barbiturates, propofol, neuroactive steroids, and etomidate, are all able at anesthetic concentrations to modulate GABAA receptor

Question 52

_{Pain Pathway​}

Usually, neurons, which transmit signals to the brain, are covered in a material called [—], which allows for very rapid transportation of signal.

Answer 52

Myelin

Myelin is a dielectric material, which forms the myelin sheath around the axons of a neuron

Cholesterol is an essential constituent in the production of myelin

Myelin is compromised of 40% water and the dry mass is about 70-85% lipids and roughly 15-30% protein

Question 53

_{Pain Pathway​}

Transmission of signal is sent from the area of stimuli via the [—] to the [—] located in the [—] horn of the spinal cord.

Answer 53

primary afferent fibers

secondary afferent neurons

dorsal (horn)

Question 54

_{Pain Pathway​}

The primary afferent terminals release [—], allowing for the signal to be transmitted upward via the secondary afferent neurons from the dorsal horn of the spinal cord to the higher centers in the brain

Answer 54

Excitatory neurotransmitters

(glutamate & substance P)

Question 55

_{Pain Pathway​}

[—] & [—] are important inhibitory neurotransmitters in terminating further transmission of signal.

Answer 55

Glycine & GABA

Question 56

_{Pain Pathway​}

There are two primary pathways that further carry the signal to the higher areas located in the brain:

Answer 56

Neospinothalamic tract & Paleospinothalamic tract

Question 57

_{Pain Pathway​}

Fast Aδ pain fibers utilize [—] tract to transmit mechanical and acute thermal pain to the [—] region of the dorsal horn. From here, the signal is crossed over and then sent up to the [—] region of the brain and then onward to the [—] areas of the cerebral cortex.

Answer 57

Neospinothalamic Tract (NT)

Lamina I region

thalamus region

somatosensory areas

Question 58

_{Pain Pathway​}

Slow C-fibers utilize [—] tract to transmit signals to the [—] regions of the [—] horn of the spinal cord. From here the signal is crossed over and then sent up to [—] area. Only one tenth to one fourth of the fibers pass all the way to the thalamus.

Answer 58

Paleospinothalamic Tract (PT)

laminae II and III regions

dorsal horn

brain stem area

Question 59

_{Pain Pathway}

Bradykinin, serotonin, prostaglandins, cytokines and H+, inflammatory meditators are released from damaged tissue and can stimulate nociceptors directly

They can also act to reduce the activation threshold of the nociceptors so the stimulation required for activation is minimal

This process is described as

Answer 59

Primary sensitization

Question 60

_{Pain Pathway}

For example, if a person is injured on the right side of the spine, the person will not be able to feel a touch on the right foot but will be able to feel pain on that foot

Likewise, the person will feel a touch on the left side of the foot but will not be able to feel pain on that foot

Why is this the case?

Answer 60

When a pain receptor detects a painful stimulus, the signal is sent down the neuron to the spinal cord, specifically the dorsal horn

Once reaching the dorsal horn, the signal is crossed over to the opposite side and then sent to the brain

Meaning that an injury to the right side of the body sends a signal that travels up the left side of the spinal cord

The switching sides structure leads to the potential of dissociated sensory loss, is caused by neurological damage caused by a lesion to the spinal cord which involves loss of fine touch an proprioception without the loss of pain and temperature or vice-versa

Question 61

_{Pain Pathway}

Nociception does not always lead to the experience of pain - The product of the brain’s abstraction and elaboration of sensory input is known as:

Answer 61

Perception

The nature of pain is highly individual and subjective, which makes it difficult to define and treat

There are no “painful stimuli” –stimuli that always elicit the perception of pain in all individuals

For instance, wounded soldiers not feeling pain until safely removed from battle or athletes not detecting injury until the game is finished

Question 62

_{Pain Pathway}

As mentioned previously pain receptors are located throughout the body, thus leading to many sources areas of pain - Pain can be either acute or chronic - Acute pain can be:

Answer 62

Intense and short-lived

Once injury is healed, pain goes away

Question 63

_{Pain Pathway}

Chronic pain is a sensation lasting much longer and ongoing condition, such as neck pain, headaches, neuropathic pain, etc. - A possible explanation for chronic pain is related to a phenomenon called:

Answer 63

Sensitization

Following continuation and prolonged noxious stimulation, the nearby silent pain neurons that were unresponsive to stimulation, actually become now active

Also, some of the chemicals produced and released at the injury site alter the physiological properties of the nociceptors

The nociceptors begin to send pain signals automatically, causing chronic pain

Question 64

_{Pain Pathway}

The following can further identify pain:Somatic Pain

Answer 64

Cutaneous, Superficial or Peripheral

Pain arising from the skin and muscles or peripheral nerves.

Pricking pain, burning and soreness pain resulting from tissue damage

Deep Pain

Pain arising from joint receptors tendons and fascia

Dull, aching or burning pain

Accompanied with sweating and nausea and changes in blood pressure and heart rate

Question 65

_{Pain Pathway}

Pain receptors are sensitive to

Answer 65

Temperature,

vibration,

stretch and

inflammation

Pain is lack of oxygen, as in ischemic muscle cramps

More localized sensation

Question 66

_{Pain Pathway}

Sudden, unexpected damage to the skin is followed by these responses:

Answer 66

*Startle response: flexion reflex, postural readadjustment and orientation of the head and eyes to examine the damaged area

*Autonomic response: release of Norepinephrine, Epinephrine, Adrenocorticotropic Hormone (ACTH), Cortisol and vasoconstriction and piloerection (involuntary erection or bristling of hairs due to sympathetic reflex triggered by cold, shock, fright)

*Behavioral response: vocalization, rubbing designed to reduce pain

Question 67

_{Pain Pathway}

Felt in the internal organs and main body cavities: thorax (lungs and heart), abdomen (bowels, spleen, liver and kidneys, and the pelvis (ovaries, bladder and the womb)

Answer 67

Visceral Pain

Nociceptors respond to inflammation, stretch and ischemia (oxygen starvation)

Free nerve endings are scattered leading to pain that is not localized but distant

Vague deep ache sensation

Question 68

_{Pain Pathway}

Pain Observed in the thalamus portion of the brain, after a stroke or occlusion in the cerebral artery

Answer 68

Thalamic Pain

Associated with intracranial pain or pressure and sensory loss

Question 69

_{Pain Pathway}

Pain Caused by damage to nerves in the central or peripheral nervous system

Answer 69

Neuropathic Pain

Commonly referred to pinched nerve or trapped nerve

Can be caused by nerve degeneration such as in stroke, multiple-sclerosis, or oxygen starvation

Possible sources: trauma or surgery, diabetes mellitus, shingles, slipped disc, chemotherapy, infection or malignancy

When nerve is injured it becomes unstable and the signaling becomes muddled and haphazard, leading the brain to interpret as pain

More likely to be spontaneous and described as burning or “like an electric shock” sensation

Other sensations experienced include numbness, pins and needles, tingling and hypersensitivity to temperature, vibration and touch

Question 70

_{Pain Pathway}

Psychic reaction to pain which includes responses to pain such as anguish, anxiety, crying, depression, nausea and excess muscular excitability throughout the body

Answer 70

Psychosomatic Pain

Reactions are variable depending on the individual

Sensation of pain can be influenced by emotions, past experiences and suggestions

Question 71

_{Pain Pathway}

Painful sensation at a site other than the injured area

Answer 71

Referred Pain

Not localized to the site of cause but at distant site

For example: pain associated with heart attack is referred to the left chest, shoulder and upper arm rather than the chest

Question 72

_{Pain Pathway}

Experience of pain without any signals from the nociceptors

Answer 72

Phantom Pain

Previous injury or amputation where sensory roots have been severed or removed, yet sensation of pain is still experienced

Question 73

_{Pain Pathway}

The series of events that follow tissue injury is called

Answer 73

Peripheral sensitization

During conditions of tissue injury, the inflammatory response can directly affect pain sensation

During the inflammatory response, release of intracellular contents from damaged cells, include (K+, H+), Bradykinin, histamine, serotonin, substance P, histamine, ATP and nitric oxide

Also activation of the arachidonic acid pathway leads to the production of prostanoids and leukotrienes

Recruited immune cells release further mediators including cytokines and growth factors

Some of these agents activate peripheral pain receptors directly that lead to spontaneous pain and the other agents act indirectly via inflammatory cells to stimulate the release of more pain-causing mediators

Question 74

_{A closer look at some of the Pain meditators}

Released during tissue injury - Produces pain, inflammation and hyperalgesia (increased sensitivity to pain)

Answer 74

Bradykinin

Question 75

_{A closer look at some of the Pain meditators}

Important to the initiation and maintenance of inflammation - May act directly on nociceptors and stimulate the release of prostaglandins

Answer 75

Cytokines

Question 76

_{A closer look at some of the Pain meditators}

Neurotrophic growth factors, including NGF, make contributions to the changes of neuron sensitivity during inflammation

Answer 76

Growth Factors

Question 77

_{A closer look at some of the Pain meditators}

Neuropeptides such as substance P and CGRP release from the distal and central terminals of neurons. (The nervous system works together with the immune system to coordinate response to tissue injury)

Answer 77

Neurogenic Factors

Wheal and flare response is indicative of the neuropeptides response by cutaneous injury

Substance P breaks down mast cells to produce histamine release

Question 78

_{A closer look at some of the Pain meditators}

Important mediators of inflammation, fever and pain - Synthesize the enzyme (cyclo-oxygenase-1) COX-1 and COX-2 - Considered sensitizing agents

Answer 78

Prostaglandins

Question 79

Immune system’s response to infection and injury is:

Answer 79

Inflammation

Inflammation is intrinsically beneficial event, which leads to removal of certain factors and restoration of tissue structure and physiological function

Question 80

Inflammation

Failure of acute inflammatory response to resolve may lead to conditions of:

Answer 80

Auto-immunity

Chronic inflammation and

Excessive tissue damage

Question 81

_{Pain Pathway}

Describing pain is a complex structure within the body - why?

Answer 81

From the various stimuli to the internal perception of pain and the signaling cascades and pathways, the human body is one marvelous design!

It is unavoidable during a lifetime that we all will experience the sensation of pain and how we perceive it as a normal and beneficial or suffering and intolerable!

Part two of the series of Pain will look in to the clinical assessment of pain by clinicians and also current and alternative solutions for the alleviation of painful symptoms.

Question 82

_{Ascending Pain Pathway}

What are the major three steps of the Ascending Pain Pathway?

Answer 82

1) Transduction
2) Transmission
3) Perception

Question 83

_{Descending Pain Pathway}

What is the major step of the Descending Pain Pathway?

Answer 83

Modulation

Question 84

_{Pain Pathway​}

Nociceptors (primary order neurons) are categorized according to the stimulus to which they respond and by the properties of the axons associated with them - Which fibers are lightly myelinated, medium-sized fibers that are stimulated by severe mechanical deformation (mechanonociceptors) or by mechanical deformation and/or extremes of temperature (mechanothermal nociceptors).

Answer 84

A-delta (Aδ) fibers

Aδ fibers rapidly transmit sharp, well-localized “fast” pain sensations

These fibers are responsible for causing reflex withdrawal of the affected body part from the stimulus before a pain sensation is perceived

Question 85

_{Pain Pathway​}

Which fibers polydomial, that is they are stimulated by mechanical, thermal, and chemical nociceptors?

Answer 85

C fibers

The smaller unmyelinated C fibers are polymodal and are stimulated by mechanical, thermal, and chemical nociceptors

The unmyelinated C fibers slowly transmit dull, aching, or burning sensations that are poorly localized and longer lasting.

Question 86

_{Pain Pathway​}

Which pain fibers transmit touch and vibration sensations?

Answer 86

A-beta (Aβ) fibers

A-beta (Aβ) fibers are large myelinated fibers that transmit touch and vibration sensations

They do not normally transmit pain!!!

Question 87

_{Spino-Thalamic Pain Pathway}

Neurons that conduct impulses from receptors of the skin and from proprioceptors (receptors located in a join, muscle or tendon) to the dorsal ganglion at the spinal cord, where they synapse with second-order neurons

Answer 87

1st order neurons

First-order neurons conduct impulses from receptors of the skin and from proprioceptors (receptors located in a join, muscle or tendon) to the dorsal ganglion at the spinal cord, where they synapse with second-order neurons

Question 88

_{Spino-Thalamic Pain Pathway}

Neurons that cross to the other side of the spinal cord and form the ascending spinothalamic tract.

Answer 88

2nd order neurons

2nd order neurons cross to the other side of the spinal cord and form the ascending spinothalamic tract

Spinal cord to thalamus

Question 89

_{Spino-Thalamic Pain Pathway}

Neurons that continue from the thalamus to the cortex

Answer 89

3rd order neurons

The 3rd order neurons continue from the thalamus to the cortex

Question 90

_{1st Order Neuron}

First-order neurons conduct impulses from receptors of the skin and from proprioceptors (receptors located in a join, muscle or tendon) to the dorsal ganglion at the spinal cord, where they synapse with second-order neurons.

When peripheral terminals of nociceptive C fibers and A-delta (Aδ) fibers are depolarized by noxious mechanical, thermal, or chemical energy, this marks the begining of:

Answer 90

Transduction

The membranes of peripheral terminals of nociceptive C fibers and A-delta (Aδ) fibers contain proteins and voltage-gated ion channels that convert thermal, mechanical, or chemical energy into an action potential (AP)

Nociceptor terminals are spread densely throughout the skin

They are found less on periosteum, joints, tendons, muscles, and least on the surface of organs

Transduction defines responses of peripheral nociceptors which can be due to mechanical stimulation, thermal injury, or chemical injuries

Noxious stimuli are converted into a calcium ion– (Ca2+) mediated electrical depolarization within the nociceptor endings

Now , the damaged cells (skin, fascia,muscle, bone, and ligaments) => lysed cell => intracellular hydrogen and Potassium release including arachidonic acid from the damaged cell membrane => accumulation of arachidonic acid stimulates COX-2 and prostaglandins are formed => prostaglandins, hydrogen and potassium play a key role in the activation of peripheral nociception => this initiate inflammatory responses and peripheral sensitization that increase tissue swelling and pain at the site of injury.

Question 91

Neurons that cross to the other side of the spinal cord and form the ascending spinothalamic tract are known as:

Answer 91

2nd order neurons

Conduct impulses from Spinal cord to thalamus

Question 92

_{2nd order neuron - Spinal cord to thalamus}

Describe the path of 2nd order neuron

Answer 92

Transmission

The second-order neuron begins with the dorsal horn of the spinal cord and decussates to the contralateral spinothalamic tract

Second-order neurons exclusively transmit noxious stimuli

2nd order neurons are most prevalent in the dorsal horn and receive signals from A-beta, A-delta, and C fibers

In the thalamus, the second-order neuron synapses with the third-order neuron that transmits to the postcentral gyrus

Question 93

_{2nd Order Neuron}

There are 2 types of nociceptor fibers that conduct APs to the spinal cord

Answer 93

A-delta fibers

A-delta fibers (Að) are slow, thin, myelinated fibers associated with sharp/pricking, well localized pain

C fibers

C fibers are very slow, thin, unmyelinated fibers that are associated with a dull, aching, throbbing, diffuse pain

Question 94

_{2nd Order Neuron}

A third type of fiber is a fast, large diameter, myelinated fiber that carries APs from mechanoreceptors

Answer 94

A-beta (Aß) fibers

A third type of fiber, A-beta (Aß), is a fast, large diameter, myelinated fiber that carries APs from mechanoreceptors

Aß fibers are believed to modulate C and Að activity within the dorsal horn

Question 95

_{2nd Order Neuron}

The dorsal horn is divided into distinct

Answer 95

Gray matter laminae

Primary afferent presynaptic terminals project into specific laminae

Question 96

_{2nd Order Neuron}

Which Lamina receives presynaptic terminals of Að and C fibers?

Answer 96

Lamina I

It also contains second order neurons that project to the thalamus and relay to somatosensory cortex and cingulate cortex

[Know the difference btw laminas I, II and V]

Question 97

_{2nd Order Neuron}

Which Lamina receives presynaptic terminals from C fibers which synapse on interneurons, aka substantia genatinosa

Answer 97

Lamina II

[Know the difference btw laminas I, II and V]

Question 98

_{2nd Order Neuron}

Which Lamina receives presynaptic terminals from Aβ fibers and dendrites from lamina V projecting neurons

Answer 98

Lamina III

[Know the difference btw laminas I, II and V]

Question 99

_{2nd Order Neuron}

Which Lamina receives presynaptic terminals from Aβ fibers and dendrites from lamina V projecting neurons?

Answer 99

Lamina IV

[Know the difference btw laminas I, II and V]

Question 100

_{2nd Order Neuron}

Which Lamina receives presynaptic terminals of Að and contains second order neurons that project to the locus coeruleus, parabrachial nucleus, amygdala and hypothalamus.

Answer 100

Lamina V

[Know the difference btw laminas I, II and V]

Question 101

_{2nd Order Neuron}

Which neurons can facilitate or inhibit transmission to second order neurons?

Answer 101

Interneurons

Question 102

_{2nd Order Neuron​}

Describe Transmission

Answer 102

The AP causes the presynaptic terminals of Að and C fibres to release a variety of pro-nociceptive substances into the synaptic cleft

C-fiber presynaptic terminals are known to release glutamate which activates postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors; substance P (SP), which activates postsynaptic NK1 receptors; and calcitonin gene–related peptide (CGRP), which activates postsynaptic CGRP receptors

Activation of postsynaptic receptors results in an influx of ions that depolarize second order neurons and interneurons

When a secondary neuron is depolarized it generates an action potential that is relayed through the contralateral spinothalamic tract (STT) or to the medulla and brain stem via the spinoreticular (SRT) & spinomesencephalic (SMT) tracts or to the hypothalamus via the spinohypothalamic tract (SHT)

Question 103

_{2nd Order Neuron​}

Postsynaptic terminals of second order neurons exhibit an array of neurotransmitter receptors

An unusual and important receptor is the N-methyl-D-aspartate (NMDA)-linked channels

NMDA channels are normally inactive because they are ordinally blocked by magnesium ions

However, intense or prolonged periods of depolarization can release the magnesium ion from the NMDA-linked channel

Loss of the Mg blockade allows an influx of calcium ions

Increased intracellular calcium ions has two important effects on the development of neuropathic disease:

Answer 103

Lowered activation threshold

The first effect leads to a lowered activation threshold and the insertion of more receptors in the postsynaptic membrane

Nitric oxide

The second effect initiates a cascade that results in the production and release of nitric oxide into the synaptic cleft

Presence of nitric oxide in the synaptic cleft causes an exaggerated release of neurotransmitters from the presynaptic terminal resulting in synaptic hyperexcitability

Question 104

_{2nd Order Neuron​}

Know which fiber releases wich substance (GABA, Glycine, Glutamine, substance P)

Know which receptor to these substnaces work on

Answer 104

…

Question 105

_{2nd Order Neuron}

Marginal zone It receives input primarily from Lissauer’s tract and relays information related to pain and temperature sensation.

Answer 105

Lamina I

Question 106

_{2nd Order Neuron}

Substantia gelatinosa (Rolando’s substance) It extends the entire length of the spinal cord and into the medulla oblongata where it becomes the spinal nucleus of trigeminal nerve. It receives direct input from the dorsal (sensory) nerve roots, especially those fibers from pain and thermoreceptors. Composed of fine networks of interneurons, it contains high levels of substance P as well a large number of opioid receptors. Thus, the substantia gelatinosa is believed to play an important role in the modulation of and/or mediation of pain perception at the spinal level.

Answer 106

Lamina II

Question 107

_{2nd Order Neuron}

Basis of the posterior horn. The neurons here are mainly involved in processing sensory afferent stimuli from cutaneous, muscle and joint mechanical nociceptors as well as visceral nociceptors. This layer is home to wide dynamic range tract neurons and interneurons.

Answer 107

​Lamina V, VI

Question 108

_{2nd Order Neuron}

The conduction of pain impulses along the Aδ and C fibers into the dorsal horn of the spinal cord and to the brainstem, thalamus, and cortex is also known as:

Answer 108

Pain transmission

Pain Fibers Terminate Primarily in Laminae II and V of the Dorsal Horn

The myelinated Aδ fibers (fast localized pain) synapse on a second set of neurons that carry the signal to the thalamus via the spinothalamic tracts

The C fibers (slow pain) synapse on laminae II and V interneurons that connect with neurons in laminae II, IV, and V and carry the pain signal to the reticular formation and midbrain via the paleospinothalamic tract

The axons of the spinothalamic tracts cross over the spinal cord to ascend in the anterior and lateral spinal cord white matter

Question 109

_{2nd Order Neuron}

The dorsal horn is divided into distinct

Answer 109

Gray matter laminae

Primary afferent presynaptic terminals project into specific laminae

Lamina I receives presynaptic terminals of Að and C fibers. It also contains second order neurons that project to the thalamus and relay to somatosensory cortex and cingulate cortex.

Lamina II receives presynaptic terminals from C fibers which synapse on interneurons,

Lamina III receives presynaptic terminals from Aβ fibers and dendrites from lamina V projecting neurons.

Lamina IV receives presynaptic terminals from Aβ fibers and dendrites from lamina V projecting neurons.

Lamina V receives presynaptic terminals of Að and contains second order neurons that project to the locus coeruleus, parabrachial nucleus, amygdala and hypothalamus

Question 110

_{2nd Order Neuron}

Which neurons can facilitate or inhibit transmission to second order neurons?

Answer 110

Interneurons

Question 111

_{Pain Pathway}

Neurons that continue from the thalamus to the cortex

Answer 111

3rd Order Neuron

They are responsible for Pain Perception

Question 112

_{3rd Order Neuron}

Perception of nociceptive pain is dependent upon

Answer 112

Neural processing in the spinal cord and several brain regions

Pain becomes more than a pattern of nociceptive action potentials when they reach the brain

Action potentials in the ascending spinothalamic tract are decoded by the thalamus, to be perceived as an unpleasant sensation that can be localized to a specific region of the body

Question 113

_{3rd Order Neuron}

Action potentials ascending the spinobulbar tract are decoded by the amygdala and hypothalamus to generate a sense of urgency and intensity - It is the intergration of sensations, emotions and cognition that result in our

Answer 113

Perception of pain

Question 114

_{Perception of pain}

Which imaging tests have enable researchers to monitor perfusion, metabolism and the sequence of activity across multiple brain structures in response to painful stimulation

Answer 114

Positron Emission Tomography (PET) and

Functional Magnetic Resonance Imaging (fMRI)

These tests demonstrate significant variation in the pattern, intensity and volume of brain activity between individuals exposed to similar painful stimulation

The findings reinforce the notion that pain is a complex individual experience that can not be quantified by anyone other than the person experiencing it

Question 115

Descending Pathway

Answer 115

4th order Neuron

Modulation

Question 116

_{Modulation: Periaqueductal Gray Matter (PAG)}

What is PAG?

Answer 116

Aka central gray

Located around the cerebral aqueduct of the midbrain

Consists of several nuclei

Plays a role in the descending pain pathway

Question 117

_{Modulation: Periaqueductal Gray Matter (PAG)}

Describe Modulation

Answer 117

Modulation of nociceptive transmission is an adaptive process involving both excitetory and inhibitory mechanisms

Modulation focuses on the processes that inhibit or suppress transduction, conduction or transmission, thereby interrupting or diminishing the perception of pain

Question 118

_{Modulation: Periaqueductal Gray Matter (PAG)}

So how does it do it?

Answer 118

The periaqueductal gray, is located in the midbrain, consists of many nuclei

Here is where enkephalins or dynorphins are being release once periaqueductal gray is activated to act on the opioid receptors

Question 119

_Modulation

Major structures involved in the Descending network.

Answer 119

(5) Periaqueductal gray
(6) Locus coeruleus => NE
(7) Caudal raphe nuclei
(8) Rostral ventrolateral medullary nuclei
(9) Dorsal motor nucleus of the vagus nerve

Green arrows: Descending projections from periaqueductal gray

Blue arrows: Descending projections from the caudal raphe and locus coeruleus

Question 120

_Modulation

Which …. represses the release of glutamate?

Answer 120

NE

Question 121

_Modulation

Central modulation of nociception involves multiple sites and mechanisms:

Answer 121

In the brainstem and midbrain, activated Mu receptors turn off GABAergic interneurons responsible for suppressing the antinociceptive decending pathway

In other words, opioids enhance the activity of the descending pathway which results in increased release of antinociceptive serotonin and norepinephrine from the descending neuron terminals into the dorsal horn

Endogenous opioids (endorphins) work in a manner similar to exogenous opioids

The existence of endorphins has been demonstrated by the application of stimulation produces analgesia (SPA)

Electrical stimulation of the periaqueductal gray (PAG) elicits the release of endorphins which produce analgesia that can be blocked by the opioid antagonist naloxone

When opioids are injected into the PAG, analgesia is produced via the descending pathway => now ECTs make more sense

Antidepressants are believed to enhance the analgesic activity of the descending pathway by increasing the availablity of synaptic monoamines

The monoamines serotonin and norepinephrine are the primary neurotransmitters released by descending pathway neuron terminals

Descending pathway neurons arise in the brainstem and terminate in close proximity to primary afferent terminals, interneurons and synaptic membrane of second order neurons located in the dorsal horn

Stimulation of the nucleus raphe magnus in the brainstem results in antinociception attributed to the release of serotonin (5-HT) within the dorsal horn

“Agents that block 5-HT synthesis attenuate stimulation-produced analgesia, and the application of some 5-HT agonists in the spinal cord results in inhibition of cells responsive to nociceptive stimuli

Stimulation of the locus coeruleus in the medulla results in antinociception attributed to the release of norepinephrine within the dorsal horn

Presynaptically noradrenaline increases inhibitory transmitters from interneurons and depresses glutamate release from both Aδ and C afferent terminals

Question 122

_{Pain Pathway}

The physiologic process of suppressing or facilitating pain is known as:

Answer 122

Pain Modulation

Pain modulation involves many different mechanisms that increase or decrease the transmission of pain signals throughout the nervous system

Depending on the mechanism, modulation can occur before, during, or after pain is perceived

Question 123

_{Pain Pathway}

The collection of cells in the gray area (dorsal horns) of the spinal cord is known as

Answer 123

Substantia gelatinosa

Found at all levels of the cord, it receives direct input from the dorsal (sensory) nerve roots, especially those fibers from pain and thermoreceptors

Rather than directly contributing efferent fibers to the anterolateral system or spinothalamic tracts, the substantia gelatinosa’s main connections appear to be to other lamina within the gray matter of the cord, including the contralateral lamina II

The substantia gelatinosa is also believed to receive input from descending fibers

Composed of fine networks of interneurons, it contains high levels of substance P as well a large number of opiate type receptors, both of which are involved in the perception of pain

Thus, the substantia gelatinosa is believed to play an important role in the modulation of and/or mediation of pain perception at the spinal level

Question 124

STIMULI THAT ACTIVATE NOCICEPTORS

Answer 124

Skin: Pricking, cutting, crushing, burning, freezing

GI tract: Engorged or inflamed mucosa, distention or spasm of smooth muscle, traction on mesenteric attachment

Skeletal muscle: Ischemia, injuries of connective tissue sheaths, necrosis, hemorrhage, prolonged contraction, injection of irritating solutions

Bone: Periosteal injury, inflammation, fractures, tumors

Joints: Synovial membrane inflammation

Arteries: Piercing, inflammation

Head: Traction, inflammation, or displacement of arteries, meningeal structures, and sinuses; prolonged muscle contraction

Heart: Ischemia and inflammation