Pain Pathways and Drug Effects

Pain Pathways

• Pain signals travel from free nerve endings to the spinal cord, then the thalamus, and finally to the somatosensory cortex for location.
• Emotionally perceived aspects of pain (how painful it feels), also travel from free nerve endings to the spinal cord, then the thalamus, and to areas like the hippocampus, amygdala, and cingulate cortex.

Anti-Pain Pathways

• Descending pathways originate in the midbrain, and include serotonin and norepinephrine.
• These neurotransmitters block pain signals at the "pain gate."
• Opioids enhance the effect of serotonin and norepinephrine.

Decreasing Pain with Drugs

• Reduce inflammation (e.g., aspirin, NSAIDs).
• Reduce nociceptor excitation (e.g., gabapentin, pregabalin).
• Reduce neurotransmitter release from nociceptors (e.g., opioids).
• Activate anti-pain pathways (e.g., antidepressants, opioids).
• Influence cognitive and emotional processing (e.g., opioids).

Terminology

• Opium: Juice from a poppy plant.
• Narcotic: Any drug causing sleep.
• Opiate: Drug extracted from Opium (e.g., morphine, codeine).
• Opioid: Endogenous ligand that binds to opioid receptors (e.g., endorphins, enkephalins, dynorphins). The term now commonly applies to both natural and synthetic drugs targeting these receptors.

Opiate Sources

• Opium is sourced from the Papaver somniferum plant.
• Native to Eurasia.
• Used for at least 7000 years.
• Laudanum is a mixture of alcohol and opium.
• Hyppdermic injection (1856) has been associated with "soldier's disease".

Opioid Functions

• Analgesia (pain relief).
• Sleep induction
• Anti-tussive (cough suppressant).
• Regulates intestinal motility.
• Synthesis: Precursor polypeptides are cleaved by enzymes (proteases) into active forms.
• Examples:
  • POMC → Endorphin
  • Proenkephalin → Enkephalin
  • Proendorphin → Endorphin, Dynorphin
• Receptors: Metabotropic (affect intracellular processes). Located in the spinal cord, brainstem, thalamus, basal ganglia, nucleus accumbens, cortex.

Opioid Receptors

• Key receptor subtypes: Mu, Kappa, Delta.
• Endogenous ligands: Endorphin, Dynorphin, Enkephalin.
• Exogenous ligands: Morphine, Naloxone, Salvinorin A, Pentazocine, Kratom

Opioid Drugs

Pure Agonists (Mu)

• Morphine, Codeine, Heroin, Methadone, Meperidine (Demerol)
• Fentanyl and derivatives are 80-500 times more potent than morphine.

Mu Antagonists

• Naloxone (Narcan): Reverse opioid overdose.
• Naltrexone (ReVia, Trexan): Used in treatment to block opioid effects.

Partial Mu Agonists

• Limits respiratory depression, abuse potential. Examples: Buprenorphine (Subutex), Tramadol (Ultram).
• Tramadol also blocks norepinephrine reuptake and releases serotonin, with an active metabolite extending its analgesic effects.

Mixed Agonist-Antagonists

• Weak Mu antagonists + Kappa agonists. Example: Pentazocine (Talwin).
• Dysphoria often limits usefulness.

Mixed Agonist-Antagonist (Partial Mu agonists + Pure Mu Antagonist)

• Suboxone: Buprenorphine + Naloxone.
• Naloxone is inactive orally but active when injected or crushed.

Explore the intricacies of pain pathways and the mechanisms by which various drugs can reduce pain. This quiz covers the journey of pain signals through the nervous system, the role of neurotransmitters, and the impact of anti-pain medications. Test your understanding of pain perception and its management.