Pain Anatomy, Physiology, and Pharmacology
Core architecture
Nociception has four steps: transduction, transmission, modulation, and perception. First-order neurons sit in the dorsal root ganglion, and their peripheral terminals carry transducer channels (TRPV1, ASICs, voltage-gated sodium channels such as Nav1.7/1.8) that convert noxious stimuli into depolarization. Aδ fibers are thinly myelinated and signal fast, sharp, well-localized "first pain"; C fibers are unmyelinated and signal slow, dull, burning "second pain." Questions frequently swap these two.
Second-order neurons live in the dorsal horn. Laminae I and II (substantia gelatinosa) are the key nociceptive relay; Aβ touch fibers normally terminate deeper in laminae III–V but can sprout into lamina II after nerve injury, a substrate for mechanical allodynia. Nociceptive-specific and wide-dynamic-range neurons project through the spinothalamic tract, which decussates near the level of entry-so a cord lesion produces contralateral sensory loss beginning one to two segments below the lesion. Spinoreticular and spinomesencephalic projections underlie arousal and the affective dimension of pain.
Modulation
Descending inhibition runs from the periaqueductal gray to the rostral ventromedial medulla (serotonergic raphe and "off-cells") and then to the dorsal horn. This circuit helps explain stress-induced analgesia and why both opioids and SNRIs relieve pain.
Pharmacology anchors
NSAIDs inhibit cyclooxygenase. Local anesthetics block voltage-gated sodium channels from the cytoplasmic side and are weak bases, so they work poorly in acidic infected tissue. Gabapentinoids bind the α2δ subunit. Opioids are mu agonists, and tolerance (needing more drug), dependence (withdrawal on stopping), and addiction (compulsive use despite harm) are three different things-a classic trap.
Rule of thumb: map every drug to its molecular target and every pain to its fiber type; most questions resolve from that mapping alone.