Module 2 Lecture 1: Mechanisms of Pain

Question 1

Front: What are the four main steps in the ascending pain pathways?

Answer 1

Back:
1. Detection of stimulus by nerve fiber endings.
2. Processing of signals in the dorsal horn of the spinal cord.
3. Transmission of response to the central nervous system (CNS).
4. CNS responses.

Question 2

Front: What is nociception and how do nociceptors function?

Answer 2

Back: Nociception is the somatic sensation that detects noxious, potentially tissue-damaging stimuli. Nociceptors are primary afferent neurons that detect these stimuli in the periphery, with cell bodies in the dorsal root ganglia (DRG). They form synapses in the dorsal horn of the spinal cord. Each nociceptor has its own receptive field, which varies in size across the body.

Question 3

Front: What types of fibers are involved in nociception, and what are their functions?

Answer 3

Back:
Aβ fibers: Non-noxious mechanical stimuli (e.g., light touch).
Aδ fibers: Noxious mechanical and thermal stimuli (e.g., sharp pain).
C fibers: Noxious heat, chemical stimuli, and slow, burning pain.

Question 4

Front: What are the primary receptors and ion channels involved in nociceptive signaling at nerve terminals?

Answer 4

GPCRs (G-protein coupled receptors): Bradykinin, prostanoids (PGE2), opiates, cannabinoids, noradrenaline.

Ion Channels: TRP, ASIC, ATP-P2X.

Tyrosine Receptor Kinases: Respond to nerve growth factor (NGF).

Voltage-Gated Ion Channels: Kv, Nav, Cav (important for action potentials).

Question 5

Front: What is the role of bradykinin in pain signaling?

Answer 5

Back: Bradykinin is a potent pro-nociceptive peptide derived from kininogen. It is activated by Kallikrein and plays a crucial role in linking tissue injury to nociception by activating bradykinin GPCRs, leading to depolarization and excitation of nociceptive neurons.

Question 6

Front: How does bradykinin signaling contribute to nociception?

Answer 6

Back: Bradykinin activates its GPCR, stimulating Gq proteins which in turn activate phospholipase C-β. This cascade leads to the activation of TRPV1 channels, resulting in depolarization and excitation of nociceptive nerve terminals.

Question 7

Front: What is sensitization, and how does it contribute to chronic pain?

Answer 7

Back: Sensitization is a form of neural plasticity at sites of tissue damage, where mediators like prostaglandins and growth factors lower the threshold for activation of nociceptors. This can lead to allodynia (pain from normally non-painful stimuli) and hyperalgesia (exaggerated response to painful stimuli). Chronic sensitization underlies conditions like neuropathic pain, causing ongoing pain even without further injury.

Question 8

Front: What is the difference between allodynia and hyperalgesia?

Answer 8

Back:
Allodynia: A normally non-painful stimulus is perceived as painful.
Hyperalgesia: An exaggerated response to a painful stimulus.

Question 9

Front: How do peripheral and central sensitization contribute to neuropathic pain?

Answer 9

Back: Sensitization of both peripheral (nociceptors) and central (spinal cord and brain) nerves decreases pain thresholds, leading to chronic pain conditions such as allodynia, hyperalgesia, and spontaneous pain, even in the absence of ongoing injury.

Question 10

Front: What role do prostaglandins play in pain signaling?

Answer 10

Back: Prostaglandins enhance the pain-producing effects of other agents like bradykinin. They also sensitize nerve terminals to other agents by inhibiting potassium (K+) channels, which leads to depolarization and increased pain perception.

Question 11

Front: How do nociceptors transduce environmental stimuli into pain signals?

Answer 11

Back: Nociceptors respond only to noxious stimuli, requiring high thresholds to activate. When activated, they produce depolarizing currents within the nerve terminals, generating action potentials that are transmitted to the central nervous system (CNS) to be perceived as pain.

Question 12

Front: What are the differences between Aβ, Aδ, and C fibers in terms of pain perception?

Answer 12

Aβ fibers: Largest, most heavily myelinated, and respond to light touch and non-noxious mechanical stimuli.
Aδ fibers: Lightly myelinated, respond to noxious mechanical and thermal stimuli (e.g., sharp, fast pain).
C fibers: Unmyelinated, conduct impulses slowly, and respond to noxious heat, chemical stimuli, and result in slow, burning pain.

Question 13

Front: How do different types of nociceptive fibers contribute to the perception of first and second pain?

Answer 13

First pain: Sharp, immediate pain mediated by Aδ fibers.
Second pain: Dull, throbbing, and prolonged pain mediated by C fibers.

Question 14

Front: What is the role of ascending pathways in pain processing?

Answer 14

Primary afferent nociceptive neurons synapse in the superficial dorsal horn.
Axons of second-order neurons cross the midline and ascend via spinoreticular and spinothalamic tracts, projecting to the brainstem and thalamus.
Third-order neurons project to the somatosensory cortex, thalamus, and limbic system.

Question 15

Front: How do descending pathways modulate pain?

Answer 15

Descending pathways originate from cortical neurons and the amygdala.
They activate neurons in the periaqueductal gray (PAG) of the brainstem.
Projections from the PAG reach the rostral ventral medulla (RVM) and the dorsal horn of the spinal cord, modulating the pain signals.

Question 16

Front: What is the function of the dorsal horn in the spinal cord?

Answer 16

tThe dorsal horn processes nociceptive information from Aβ, Aδ, and C fibers, which synapse in laminae I, II, IV, and V.
Local circuit neurons can be inhibitory or excitatory, affecting the autonomic nervous system and motor neurons involved in withdrawal reflexes.

Question 17

Front: Explain the gate control theory of pain.

Answer 17

Inhibitory neurons in lamina II of the dorsal horn regulate pain perception.
Stimulation of Aβ fibers (e.g., by a soft touch) activates inhibitory neurons that release GABA and glycine, closing the “gate” and reducing pain.
Stimulation of small C fibers (e.g., by a painful stimulus) inhibits these inhibitory neurons, opening the “gate” and allowing pain to be perceived.

Question 18

Front: What is neuropathic pain and what conditions are associated with it?

Answer 18

Neuropathic pain arises from neurological disease of the sensory pathway and persists even after the injury is resolved.
Associated conditions include stroke, multiple sclerosis, nerve compression and damage, diabetic neuropathy, and herpes zoster infection.
It involves altered ion channel expression, damage to peripheral nerves, and reductions in inhibitory neurotransmission.
Symptoms include allodynia (innocuous touch perceived as painful) and hyperalgesia (exaggerated response to painful stimuli).

Question 19

Gabapentinoids

Answer 19

Gabapentinoids (e.g., Pregabalin, Gabapentin):
Function: Used primarily to treat neuropathic pain.
Mechanism: Inhibit voltage-gated calcium channels in the dorsal horn of the spinal cord, reducing excitatory neurotransmitter release (e.g., glutamate).
Effect: Decreases overall excitatory output, providing pain relief. They are particularly effective for conditions like diabetic neuropathy and post-herpetic neuralgia.
Efficacy: Provides about 50% pain relief in 1 out of 4 patients. Often recommended when first-line analgesics (e.g., NSAIDs or opioids) are ineffective​.

Question 20

Opioids

Answer 20

opioids (e.g., Morphine, Fentanyl, Codeine):
Function: Used for moderate to severe pain management.
Mechanism: Bind to opioid receptors (μ, δ, κ) in the CNS, inhibiting pain signal transmission. This results in activation of descending inhibitory pathways and suppression of pain perception.
Effect: Provide strong analgesia but are associated with risks like tolerance, dependence, and respiratory depression.
Types:
Morphine: Widely used for acute pain.
Fentanyl: Potent opioid, often used in anesthesia.
Methadone: Used for both pain relief and as a substitute for opioid addiction.
Side Effects: Euphoria, sedation, respiratory depression, and constipation. Long-term use can lead to addiction and tolerance​.

Question 21

NSAIDS

Answer 21

NSAIDs (e.g., Ibuprofen, Aspirin, Celecoxib):
Function: Alleviate mild to moderate pain and reduce inflammation.
Mechanism: Inhibit cyclo-oxygenases (COX-1 and COX-2), which are enzymes involved in the synthesis of prostaglandins that cause pain and inflammation.
Effect: Decrease pain sensitization by reducing the production of prostaglandin E2.
Applications: Effective for inflammatory pain conditions like arthritis and musculoskeletal injuries.
Side Effects: Gastric irritation, renal issues, and increased risk of cardiovascular events (especially COX-2 inhibitors like celecoxib)​.

Question 22

ANTIDPRESSANTS

Answer 22

Antidepressants (e.g., Amitriptyline, SSRIs, SNRIs):
Function: Used for chronic pain management, especially neuropathic pain.
Mechanism: Inhibit reuptake of serotonin and norepinephrine, increasing their levels in descending inhibitory pathways.
Effect: Enhance the inhibition of pain signals at the level of the spinal cord, reducing overall pain sensation.
Types:
Tricyclic Antidepressants (TCAs): Such as amitriptyline, are often used first-line for neuropathic pain.
Selective Serotonin Reuptake Inhibitors (SSRIs): Like fluoxetine, are less effective but have fewer side effects.
Side Effects: Dry mouth, dizziness, and sedation with TCAs; nausea and insomnia with SSRIs​.

Question 23

GlyT2 Inhibitors

Answer 23

GlyT2 Inhibitors (e.g., N-arachidonyl glycine, Oleoyl-D-lysine):
Function: Investigational drugs for neuropathic pain.
Mechanism: Inhibit GlyT2 (glycine transporter 2), increasing glycine concentration at inhibitory synapses in the dorsal horn.
Effect: Enhance glycinergic inhibition, which is often lost in chronic pain states, reducing nociceptive transmission and hyperexcitability of pain pathways.
Key Research Findings: Oleoyl-D-lysine showed significant analgesic effects in animal models of neuropathic pain without major side effects​.

Question 24

local anaesthetics

Answer 24

Local Anesthetics (e.g., Lidocaine, Procaine):
Function: Block acute pain at localized areas.
Mechanism: Inhibit voltage-gated sodium channels in sensory neurons, preventing action potential generation and pain transmission.
Applications: Used in dental procedures, minor surgeries, and topical pain relief (e.g., lidocaine patches).
Side Effects: Usually minimal but can include numbness or, in rare cases, systemic effects if absorbed in large amounts​.

Question 25

other medications

Answer 25

Other Medications/Compounds:
Capsaicin: Depletes substance P from nerve terminals, reducing pain transmission over time. Used topically for conditions like post-herpetic neuralgia.
N-arachidonyl-glycine: Endogenous glycine derivative with unclear analgesic mechanisms. Inhibits GlyT2 and stimulates glycine receptors, contributing to its pain-relieving effects​.