Physiology and Autonomic System Overview

NSG 7430/7204 Week 8 Lecture 1

• Weekly objectives include Drives and Emotions, Limbic System Functional A&P, Limbic System Dysfunction, Sleep & Wakefulness, Hypothalamic Pituitary Adrenal (HPA) Axis, and The Stress Response.
• The Limbic System is a complex set of structures that bridge the neocortex and hypothalamus, involved with multiple functions
• The Limbic System has many areas, including the insular lobe, association cortices, basal nuclei, prefrontal cortex, and diencephalon.
• The Limbic System is involved in the stress response, homeostatic balance, emotion, and memory.
• The Hypothalamus is part of the diencephalon, and controls the pituitary gland and related functions (0.3% of total brain mass)
• Outside physiological limits, biochemistry does not function optimally, and includes examples shown like temperature, blood glucose concentrations, and oxygenation levels.
• Drives are physiological needs that create a desire for action for survival and reproduction.

Homeostasis

• Homeostasis is the physiological body's set interthreshold ranges, essential to normal biochemical function.
• Body parameters like temperature, blood pH, blood pressure, and others need to remain within these ranges for optimal bodily function.

Weekly Objectives Week 8 Lecture 2

• Drives and Emotions
• Limbic System Functional A&P
• Limbic System Dysfunction
• Sleep & Wakefulness
• Hypothalamic Pituitary Adrenal (HPA) Axis
• The Stress Response

Weekly Objectives Week 9 Lecture 1

• Functional A&P of the Sensory System
• Nociception Pathways
• Acute Pain Epidemiology & Impact
• Acute Pain Interventions
• Selected Pathophysiology: Risk Factors for Acute Pain Persistence/Transformation

Weekly Objectives Week 9 Lecture 2

• Functional A&P of the Sensory System
• Review
• Nociception Pathways
• Acute Pain: Nociceptive Physiology and Interventions
• Selected Pathophysiology: Risk Factors for Acute Pain Persistence/Transformation

Neurobiology: Pain Pathways & Interventions

• Overview of pain pathways and interventions.
• Peripheral mechanisms
• Spinal mechanisms
• Supraspinal mechanisms
• Targeted interventions

Peripheral Pain Physiology - Nociceptors

• Nociceptors are free nerve endings that detect noxious stimuli.
• Nociceptors convert (transform/transduce) the energy of noxious stimuli into an electrochemical signal.
• Analgesic targets include receptors and the transmission of neuronal fibers to the spinal cord.

Primary Somatosensory Afferent Neuronal Fibers

• A-beta fibers transmit pain response for touch and pressure (non-noxious).
• A-delta fibers transmit noxious mechanical stimuli and sub-noxious temperature stimuli.
• C fibers transmit noxious stimuli, including heat, mechanical, and chemical.

Fiber Summary - Anterolateral Pathway Reference

• The classic lateral spinothalamic pathway uses non-myelinated C fibers and thinly myelinated A delta fibers for transmitting pain, temperature, and other sensations
• The posterior column-medial lemniscus pathway serves thicker, faster myelinated fibers (A-beta and other similar fibers) for transmitting touch, vibration, and proprioception.

Primary Afferent Neurochemistry Targets

• TRP Vanilloid Type 1 Channels (TRPV1) are pain receptors for capsaicin and heat.
• Voltage-gated Nat and K+ channels initiate and transmit nociception.
• Voltage-gated Ca2+ channels are a target for pain management.
• G-coupled protein receptors modulate inflammatory mediators, such as CGRP, bradykinin, and prostaglandins (excitatory) and opioids, and adrenergic agonists (inhibitory).

Primary Nociceptive Peripheral Afferent Physiology

• When exposed to noxious stimuli, nociceptors initiate a chain reaction that includes the release of various chemicals by damaged cells.
• Release of chemical mediators causes the "triple response of Lewis" (flare, wheal, and hyperalgesia).

Primary Peripheral Afferent – Facilitory Modulation

• Nociceptors that have been stimulated can release neuromodulatory proteins to trigger the recruitment of additional nociceptors (that are typically silent under normal conditions).
• These released neuromodulatory proteins (e.g., substance P, neurokinin A, CGRP, and neurotrophins) are involved in facilitating nociception.

Consequences of Peripheral Neuronal Sensitization

• Decreased threshold and latency
• Increased frequency response
• Increased receptive field plus overlap
• After-discharges
• Increase in excitatory nociceptive transmission within the SC
• Recruitment of further neurons
• Increased neurotransmitter release locally and upstream

Spinal Nociceptive Mechanisms

• Nociceptors transmit pain signals through the dorsal horn, via Rexed's laminae.
• Glutamate is the primary neurotransmitter involved.
• GABA and glycine are inhibitory neurotransmitters.
• The substantia gelatinosa in laminae II plays a crucial role in modulating nociception.

Spinal Cord Cascade-Facilitory Modulation

• C-fibers can trigger release of excitatory neurotransmitters (glutamate and substance P).
• Activation of certain channels (e.g., Na+) can increase the temporal and spatial summation of noxious stimuli.
• This leads to neuronal sensitization and the development of persistent pain conditions.

Spinal Cord Synapse Receptors

• Key excitatory receptors: Glutamate (NMDA, AMPA, kainate, mGluR), substance P.
• Key inhibitory receptors: GABA, glycine, serotonin (5-HT).
• Alpha2-adrenergic and opioid receptors also play a significant role

Glutamate

• Continued nociceptor activity leads to prolonged glutamate release.
• Increased activity of NMDA, AMPA, and mGluR receptors.
• Calcium influx into secondary afferent neurons.
• Long-term sensitization through mechanisms like NO and prostaglandins.
• Chronic inflammation and opioid tolerance are linked to NMDA receptor activation.

Sequence of NMDA Receptor Activation

• Removal of Mg2+ block.
• Calcium influx.
• Neurotransmitter release.
• Activation and/or production of intracellular second messengers.
• Facilitation of pathway transmission.
• Gene transcription in the cell's nucleus.
• Increased responsiveness.
• Production of arachidonic acid (AA) metabolites.

sP Receptor Activation

• Excitatory amino acid cascade is activated in spinal cord and peripheral afferents.
• NK-1 receptors are crucial for mediating peripheral and spinal neuronal sensitivity involved in visceral sensations.
• Ongoing nociceptor activity is maintained throughout the body from the periphery to the SC.

Supraspinal Mechanisms

• Pain is perceived and localized via supraspinal structures (e.g., the reticular formation, hypothalamus, midbrain and others).
• Descending pathways for pain modulation originate from higher brain centers (the limbic system, prefrontal cortex)
• The pathways involve neurotransmitters like glutamate, 5-HT, endogenous opioids, norepinephrine, cannabinoids, GABA, and glycine to modulate nociceptive transmission.

Double-edged Sword

• Divergent pain signaling to important areas by the central nervous system is modulated (inhibited) by descending inhibitory pathways.
• Glutamate and other excitatory transmitters involved.
• Serotonin and other neurotransmitters crucial in pain modulation.

Supraspinal Descending Inhibition

• Brain and other structures modulate the nociceptive transmission.
• Cortical structures (e.g., PFC, insula, anterior cingulate cortex, amygdala); associated with descending inhibition of pain.
• Subcortical structures like the midbrain PAG, pontine parabrachial complex and locus coeruleus, medulla (RVM), and SC interneurons involved.

Global Actions- Main Pathway Descending Inhibition

• The PAG is stimulated by ascending pain signals and other inputs
• PAG activates structures in the parabrachial and RVM nuclei.
• RVM raphe nuclei is the final relay for descending inhibitory influence.
• Inhibitory neurotransmitters release in the spinal cord.

Nociceptive Modulation

• Excitatory amino acids (glutamate and aspartate) and substance-P initiate a cascade in response to nociceptive transmission
• Descending pathways from the brain can help inhibit this cascade, involving neurotransmitters such as GABA, glycine, and opioids.

Overview of Chronic Pain (CP) Conceptual Summary

• Persisting noxious stimuli can contribute to chronic pain through peripheral and central sensitization.
• Central structures (spinal cord, brainstem, midbrain) and cortical structures (limbic system, prefrontal cortex).
• Induction of central plasticity (particularly affecting WDR neurons in spinal cord) is involved.
• Chronic pain can lead to structural changes in the CNS and peripheral nervous system after prolonged stimuli
• Psychological mechanisms may contribute to the development or maintenance of chronic pain.

Special Issues in Chronic Pain Rx

• Opioid prescribing practices.
• The shift from an endorsement of widespread opioid use to a more cautious approach.
• The role of evidence-based medicine in guiding treatment decisions.

Sobering Facts - Substance Use

• High number of opioid-related deaths.
• Opioids strongly linked with addiction.
• Synthetic opioids play a sizable role in overdose deaths.

Things to Ponder...

• America's significant role in global opioid consumption.
• Responsibility of providers and pharmaceutical companies.

Evaluation of Potential CP Patient

• Multifactorial evaluation including a thorough medical, surgical, social, and family history (including current and past medications).
• In addition to the history, a focused neurological exam is important to assess any potential neurological involvement, including pain symptoms over time.

Common Diagnostics

• Blood tests to evaluate organ function (e.g., renal and liver function, thyroid function)
• Drug screens and other chemical assays.
• Imaging techniques (e.g., X-rays, CT scans, MRIs).

Specific Neuro Diagnostics

• Electromyography (EMG) and nerve conduction studies (NCS) to evaluate nerve dysfunction.

Thermography

• Detects heat via infrared energy emitted by body surfaces.

Chronic Pain Team Members

• An interdisciplinary approach is crucial for effective management of chronic pain.

Persistence of Acute Pain

• Estimates for prevalence of chronic pain in various procedures.

CP ~ Preoperative Risk Stratification

• Clinical risk factors that can predict chronic pain after surgical procedures or trauma

CP ~ Pre-incisional Risk Stratification

• High-dose opioid use is a potential trigger for OIH (opioid-induced hyperalgesia).
• Interventions aimed at preventing CNS plasticity induction and neuronal sensitization are essential.

CP ~ Postoperative Risk Stratification

• Early and significant pain is a risk factor
• Patients with neurotoxic chemo exposure more at risk.
• Alteration of immune function can cause hyperalgesia and increase pain severity.

Gabapentin and Pregabalin

• Effective, in some cases, as preemptive pain management agents, particularly for neuropathic pain.
• Work on inhibiting various neurotransmitters, including GABA (inhibitory) and others, acting presynaptically and postsynaptically within the SC and/or other CNS sites

Postoperative CP Risk Mitigation

• Effective anesthetic and analgesia methods for postoperative pain management.
• Multimodal strategies; including analgesics, nerve blocks, and continuous wound infiltration, to prevent or mitigate the development of prolonged pain.
• Considerations: specific regional or neuraxial approaches that may decrease the amount of opioid use for managing pain

Balanced, Preemptive Multimodal Analgesia

• Modalities that act on diverse pain pathways, increasing efficacy and reducing risks.
• Initiating interventions before the actual surgical procedure.
• Preventing prolonged noxious stimuli or at least most excessive periods.

Clinical Example (C-section Protocol)

• Example steps of anesthetic and pain management regimen for a C-section.
• Use of various drugs and techniques that are utilized for management.

Selected Pain Syndromes

• General descriptions of pain syndromes.
• Emphasis on treatment and management issues.

Entrapment Syndromes

• Entrapment of nerves where they go through a narrow passage or proximity with other structures can cause various symptoms (often lasting pain, numbness).
• Diagnoses usually rely on nerve conduction testing and imaging methods, and sometimes require surgical intervention
• Treatment involves addressing inflammation, immobilization, and potentially surgical decompression of affected tissues.

Myofascial Pain Syndromes

• Defined trigger points within muscle groups.
• Treatment involves medication, therapy (massage, PT).

Typical Presentation of Lumbar Radiculopathies

• Symptom presentation as it relates to the affected spinal nerve root.
• Associated weakness and reflexes, including pain, depending on the level of injury or lesion

Diabetic Peripheral Neuropathy

• Issues with nerve structure and blood vessel health.
• Diagnosis relies on symptom reports and nerve conduction tests
• Treatment options focus on mitigating complications and improving nerve health.

Complex Regional Pain Syndromes

• Pain syndromes with autonomic involvement, especially hyperalgesia and allodynia..
• Characterized by intense, prolonged pain, often with autonomic symptoms and reduced range of motion..
• Treatment options emphasize sympathetic nerve blocks, various pharmacological measures, and physiotherapy.

Headaches- Sinus, Cluster, Tension/Migraine

• Descriptions of the types of headaches, including their characteristics, etiology and associated complications
• Identification, and management strategies including medication, and other specialized care

Sphenopalantine Ganglion Block

• Description of the anatomical area and procedure.
• Indications, and complications.

Other Techniques, Radical Treatment Options

• Various newer interventional and surgical techniques that are used in the management of chronic pain or complicated pain.

Interdisciplinary Modalities/Team Members

• Multidisciplinary approach to chronic pain management
• Team members and roles should be incorporated

What matters in Anesthesia?

• Key considerations when treating patients expected to have various pain syndromes.

Opioid Minimization vs. Opioid-Free

• Importance of recognizing the effects of chronic opioid exposure to patients.

Opioid Efficacy

• Opioid efficacy can vary due to many factors, including patient responses to the drugs, how they are administered, and prior conditions.
• Risk factors for dependence and aberrant medication usage.

Opioids Use in Oncology Care

• The use of opioids in cancer treatment for pain relief is complex, due to a combination of immune system effects, and other tumor-related changes.

Chronic Opioid Use

• Repeated opioid use leads to structural changes in the CNS, and sometimes to worsening pain sensations.
• Mechanisms of how opioids lead to increased pain symptoms and sensitivity

OIH(Opioid Induced Hyperalgesia)

• This is a significant side effect of opioids that can lead to increased pain sensations as a consequence of extended use in some patients.

Diagnosis & Treatment of Chronic Pain

• Multifactorial evaluations are essential.
• This includes neurological, imaging, and blood tests, along with determining psychological and social factors impacting pain.

Pain Assessment

• Various pain scales can be used for evaluating and addressing patient needs
• Non-verbal communication should be evaluated when determining the effectiveness and safety of treatment.

Individualizing Pain Regimens

• Tailoring opioid and other analgesic treatments to individual pain responses to enhance efficacy.
• Individual differences in pain perception and management needs should be considered.
• Genetic and gender influences on opioid responses, effectiveness, and efficacy

Overall Chronic Pain Pathogenesis

• Sustained/prolonged nociceptive neuronal plasticity is involved.
• Peripheral and central sensitization factors influence the persistence/development of chronic pain.

Chronic Pain AP&P

• Nociceptive and neuropathic types of chronic pain, including hyperalgesia and allodynia.

Peripheral Sensitization

• Release of various substances due to nerve damage/inflammation including histamine and others that amplify pain
• Mediated by histamine, serotonin, bradykinin, prostaglandins and other chemicals within the periphery, and some neurotransmitters into the nervous spinal cord.

Central Sensitization

• WDR(wide dynamic range) neurons are key
• Activation of these neurons can be triggered by many substances that cause an increase in pain perception, including glutamate and others.
• These substances lead to prolonged glutamate and other neurotransmitter release in the spinal cord.

Glutamatergic Facilitation

• Prolonged glutamate release due to chronic nociceptor activity leads to cellular changes.
• These changes can cause widespread, long-lasting pain sensitization that amplifies pain sensation throughout the body

Inhibitory Modulation in the SC, Segmental and Supraspinal Descending Inhibition

• Methods of pain modulation, including mechanisms of how different substances inhibit neuronal pathways or pain transmission.

CP Conceptual Summary

Summary of the various mechanisms, factors, and considerations of chronic pain sensitization, induction and/or maintenance

Pain Syndromes

• Descriptions of various pain syndromes, including specific symptoms patterns.

Opioid Prescribing

• Historical opioid use and its implications.