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Pain Pathway

Two mechanism:

Excitatory Mechanisms = Ascending pathway

Inhibitory Mechanisms – Descending pathway


Pain Pathway

Excitatory Mechanisms = Ascending pathway

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).


Pain Pathway

Inhibitory Mechanisms – Descending pathway

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


Terminologies - Acute and Chronic Pain - Basic Concepts

Pain may be divided into two broad categories:

Physiological & Pathological pain




Terminologies - Acute and Chronic Pain - Basic Concepts

Physiological pain = acute pain

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



Terminologies - Acute and Chronic Pain - Basic Concepts

Pathological pain = chronic pain

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

It is "pain" as a disease


Terminologies - Acute and Chronic Pain - Basic Concepts

Non-malignant chronic pain is frequently classified into

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)


Terminologies - Acute and Chronic Pain - Basic Concepts

Malignant pain is related to

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


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:



[The International Association for the Study of Pain (IASP)]

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


Acute and Chronic Pain - Clinical Concepts: Definitions and Prevalence

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


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


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?

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)


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

Pain complaints




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?

Biological (tissue damage)

Cognitive (memory, expectations)

Emotional (anxiety, depression)

Environmental factors (reinforcement, conditioning)


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

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.


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?

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


Acute and Chronic Pain - Pain Management

Drugs currently used in clinical pain treatment include


Nonsteroidal anti-inflammatory drugs (NSAIDs)

Serotonergic compounds

Antiepileptics, and



Acute and Chronic Pain - Pain Management

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

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


Acute and Chronic Pain

Types of pain include:

•Nociceptive Pain

•Somatic Nociceptive Pain

•Visceral Nociceptive Pain

•Referred Visceral Pain



•Neuropathic Pain



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?

Nociceptive pain



Types of Pain

What are the phases of Nociceptive pain?






Types of Pain

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

Somatic nociceptive pain


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

Visceral nociceptive pain


Types of Pain

Pain that radiates in a somatic dermatomal pattern. Example MI

Referred visceral pain


Types of Pain​

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

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


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


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



Types of Pain​

Hyperesthesia is a term that encompasses both

Allodynia & Hyperalgesia


Types of Pain​​

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


Normally, allodynia subsides as healing progresses

Often you will hear Allodynia in association with Multiple Sclerosis



Exogenous opioids like hydromorphone, morphine and oxycodone produce analgesia by


mimicking endogenous endorphins



Opioids are able to activate which endorphin receptors?

Mu, Kappa & Delta




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?

Mu receptors