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Editor's Notes

1. Activation of peripheral pain receptors, also called nociceptors, by noxious stimuli generates signals that travel to the dorsal horn of the spinal cord via the dorsal root ganglion. From the dorsal horn, the signals are carried along the ascending pain pathway or the spinothalamic tract to the thalamus and the cortex. Pain can be controlled by pain-inhibiting and pain-facilitating neurons. Descending signals originating in supraspinal centers can modulate activity in the dorsal horn by controlling spinal pain transmission.1,2 Gottschalk A, Smith DS. New concepts in acute pain therapy: preemptive analgesia. Am Fam Physician. 2001;63:1979-1984. Fields HL, Martin JB. Pain: pathophysiology and management. In: Fauci AS, Braunwald E, Isselbacher KF, et al, eds. Harrison’s Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill; 1998:53-58.   
2. <<Animated slide: Please advance to view entire sequence.>> The pain response is a complex process that involves both the peripheral nervous system (PNS) and the central nervous system (CNS). Tissue injury results in the activation of the PNS. Signals from the PNS travel into the CNS. They move through the spinal cord before traveling to the brain, where pain perception occurs. In addition, pain perception can be transmitted directly from the site of injury to the CNS via a humoral signal (probably via interleukin [IL]-6), which then induces cyclooxygenase (COX)-2 in the CNS.1 This concept will be discussed in greater detail later in the presentation. Samad TA, Moore KA, Sapirstein A, et al. Interleukin-1-mediated induction of COX-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature. 2001;410:471-475.
3. Transducer receptor/ion channel complexes on peripheral nociceptor terminals respond to noxious stimuli from mechanical, chemical, or heat sources by generating depolarizing currents. If the current is sufficient, action potentials are initiated and then conducted to the CNS, where they invade central nociceptor terminals and cause the release of neurotransmitters, thus eliciting pain perception. Depicted here is the activation of vanilloid receptor VR1 by noxious heat stimuli, resulting in the generation of action potentials that travel to the spinal cord to cause the release of transmitters.1 Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765-1768.
4. Modulation is a result of receptor/ion channel phosphorylation, which causes a change in the expression of channels on the surface of primary sensory neurons. Sensitizing agents such as prostaglandin E2 (PGE2) and bradykinin released during tissue damage or by inflammatory cells sensitize nociceptor terminals. Nociceptors undergo modulation as a result of simultaneous activation of the intracellular kinase protein kinase A (PKA) or protein kinase C (PKC), the phosphorylation of a tetrodotoxin (TTX)-resistant sensory neuron–specific sodium ion channel (SNS; also referred to as SNS/PN3), and possibly the phosphorylation of VR1. Phosphorylation of SNS channels causes an influx of sodium ions. Consequently, the excitability of nociceptor terminal membranes increases, and peripheral nociceptors become more sensitive to subsequent stimuli.1 Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765-1768.
5. Following mild noxious stimuli, dorsal horn neurons are activated primarily by fast excitatory postsynaptic potentials (EPSPs) produced by unmyelinated nociceptive C-fibers. These fast EPSPs signal the onset, duration, intensity, and location of the stimulus. More intense stimuli generate higher frequency inputs and cause the synaptic release of glutamate and other neuromodulators, such as substance P, from the C-fibers to act on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). This produces slow EPSPs lasting tens of seconds.1 Repeated stimulation allows for temporal summation of slow EPSPs, resulting in the removal of the magnesium blockade on N-methyl D-aspartate (NMDA) channels.1 The increased current through the NMDA channels enhances the cumulative depolarization caused by slow EPSPs. The result is a “windup” of action potential discharge on central pain-projecting neurons and neuronal modulation.1,2 Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765-1768. Schwartzman RJ, Grothusen J, Kiefer TR, et al. Neuropathic central pain: epidemiology, etiology, and treatment options. Arch Neurol. 2001;58:1547-1550.