Untitled Flashcards Set

Primary Afferents - neurons that detect sensory information in the periphery from the skin to spinal cord

• They synapse onto the secondary afferent which passes the sensory information to the brain

Motor Efferents - take motor commands from the brain and send them to the periphery 

Nociceptors - primary afferents that only respond to pain and densely innervate every surface of the body

• All pain receptors are embedded in nociceptors

Polymodal nociceptors - detect all kinds of stimuli 

How does the skin detect pain?

• Different types of painful stimuli are detected by specific receptors expressed on polymodal nociceptors

Transient Receptor Potential (TRP) Channels

• Temperature sensitive ligand-gated ion channels

• Different types are tuned to specific temperatures

1. TRPM8 - activated/opened at temperatures below 10℃ and can be opened by the ligand menthol

2. Activated at temperatures above 43℃ and can be opened by the ligand capsaicin

Other receptors respond to inflammatory molecules to cause pain 

• Bradykinin, cytokines, prostaglandins

During immune responses, the immune cells release signalling factors that bind to nociceptors to activate them and cause pain

• Following tissue injuries or infections

• Inflammation = pain

Inflammation

Arachidonic Acid - fatty acid in the phospholipids of cell membranes that is freed when there is damage or infection by the enzyme phospholipase A2

• Important mediator in the inflammatory response of pain released in response to injury or infection

Phospholipase A2 - essentially cuts arachidonic acid out of the membrane

2 Pathways for Arachidonic Acid (Enzymes)

1. Cyclooxygenase-1 (COX1)

2. Cyclooxygenase-2 (COX2)

• Metabolizes arachidonic acid into prostaglandins (PG) and thromboxanes (Tx) that have a diverse function in the body

Prostaglandin E2 (PGE2)

• Important in inflammation and pain

• Vasodilator that can cause swelling and edema

• Can cause pyrogenic (fever)

• Attracts immune cells (leukocytic) to coordinate immune response

• Helps produce gastric mucous to maintain optimal gastric pH (independent of inflammation/pain)

Thromboxane A2

• Signals platelets to clot

• Causes vasoconstriction 

Different tissues will express either COX1 or COX2

COX1 - non-inflammatory cells (blood vessels, platelets, gastric mucosa)

COX2 - inflammatory cells

Enzyme activity is either constitutive (always on) or inducible and activated by stimulus

COX1 Constitutive - stomach, intestine, kidney and platelet

COX2 Constitutive - brain, spinal cord, kidney and testes

COX1 Inducible - kidney and inflammatory sites (macrophages, synoviocytes, endothelial cells)

Aspirin and Non-selective NSAIDs (ibuprofen or naproxen)

• Nonselective because they target both COX1 and COX2 and inhibit inflammation caused by these enzymes

• Decrease prostaglandin production inhibiting inflammation and reducing pain

• Suppress prostaglandin synthesis in the brain to reduce fever

• Daily Asprin use can prevent platelet aggregation by interfering with the thromboxane A2 pathway for those at risk of stroke or heart attack

• Most NSAIDs inhibit the catalytic site of cyclooxygenase (where arachidonic acid binds)

• Asprin (acetylsalicylic acid) is an irreversible inhibitor and binds covalently to the catalytic site of COX1 and COX2 which explains the long half-life as it inhibits platelet aggregation (96 hours) and are anucleated that can not make new proteins very slowly

• Aspirin for pain has a lower half life (4-6 hours) because new immune cells can divide quickly and the effects are blocked or reversed quickly 

Non-selective NSAIDs

• Cause gastric toxicity by inhibiting COX1 enzymes for gastric mucosa leading to gastric ulceration, upper GI bleeding and renal failure (production of PCE2)

• Toradol (ketoralac) is highly efficacious but causes issues with chronic use

• To bypass gastric toxicity, specific COX2 inhibitors have been developed but can cause a higher risk of cardiovascular toxicity

Acetominophen

• Weak and reversible COX1 and COX2 inhibitor, also inhibits COX3 that is mainly found in the cerebral cortex

• Analgesic and antipyretic but lacks the anti-inflammatory effects

• Negligible toxicity at therapeutic doses but an overdose in patients with liver impairment can cause liver damage and death

Drugs that Block Sensation

Cocaine - first local anesthetic introduced as topical but it can cause addiction and toxicity

Procain, lidocain and bupivicaine are used now with modifications to not enter the brain

• Shared chemical structure with a hydrophobic aromatic region, linker region and substituted amine (hydrophilic)

• The hydrophobic region allows it to get through membranes

• Linker region susceptible to Esterases which determines if the drug is short or long acting (determine the pharmacological effect)

Topical Anesthetics

• Bind reversibly to a specific site within the pore of sodium channels to block ion movement and inhibit action potentials

• Only accessible intracellularly

• Hydrophobicity increases the potency and duration of action because the sodium channel binding pocket is hydrophobic

• Neurons require sodium channels for action potentials and inhibiting it blocks all sensation and can cause motor paralysis

• Have a higher affinity for open channels and will block the action potential

• Anaesthetic effects are amplified in neurons that are firing a lot of action potentials and is more likely to occur in pain receptors

Drugs that Block Pain

• Different types of stimuli are detected by specific receptors expressed on polymodal nociceptors

• TRPV1 receptor responds to capsaicin which is an agonist and causes moderate burning pain 

• Chronic activation of TRPV1 receptors leads to desensitization and loss of TRPV1 nociceptors causing analgesia

• Exceeding the capacity of positively charged ions damages the nerve fibers

• Common for joint pain

• Reversible and stopping allows the peripheral endings to grow back and reinnervate skin