Modified from Woolf CJ; American College of Physicians; American Physiological Society. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med 2004;140:441-451.

Adaptive Pain

“The good”

Pain that contributes to survival by protecting the organism from injury or promoting healing when injury has occurred (nociceptive pain)

Coupled from a noxious stimulus or healing tissue

Maladaptive Pain

“The bad and the ugly”

An expression of the pathologic operation of the nervous system (neuropathic pain) or abnormal operation of the nervous system (functional pain)

Uncoupled from a noxious stimulus or healing tissue

Pain as disease

Multiple mechanisms that can produce pain, as follows:

Nociception: The sole mechanism that causes nociceptive pain and is comprised of the processes of transduction, conduction, transmission, and perception.

Transduction: The conversion of a noxious thermal, mechanical, or chemical stimulus into electrical activity in the peripheral terminals of nociceptor sensory fibers. This process is mediated by specific receptor ion channels expressed only by nociceptors (Fig. 2-3).

Conduction: The passage of action potentials from the peripheral terminal along axons to the central terminal of nociceptors in the central nervous system.

Transmission: the synaptic transfer and modulation of input from one neuron to another (Fig. 2-4).

Central sensitization: Contributes to inflammatory, neuropathic, and functional pain (Figs. 2-3 and 2-5).

Figure 2–3 A, The peripheral terminal of a nociceptor sensory neuron. The different transducing receptor and ion channels that respond to thermal, mechanical, and chemical stimuli are shown. MDEG, mammalian degenerin; P2X, purinergic receptor; TRM3, 2’-O-ribose methyltransferase 3. B, The mechanism of peripheral sensitization. Inflammatory mediators, such as prostaglandin E₂ (PGE₂), bradykinin (BK), and nerve growth factor (NGF), activate intracellular kinases in the peripheral terminal that phosphorylate transducer channels to reduce their threshold or sodium channels to increase excitability. C, Transcriptional changes in the dorsal root ganglion (DRG). Activity, growth factors, and inflammatory mediators act on sensory neurons to activate intracellular transduction cascades. These cascades control the transcription factors that modulate gene expression, leading to changes in the levels of receptors, ion channels, and other functional proteins. AA, arachidonic acid; ASIC, acid-sensing ion channel; ATP, adenosine triphosphate; CaMKIV, calcium/calmodulin-dependent protein kinase IV; Cox2, cyclooxygenase-2; ERK, extracellular signal-regulated kinase; EP, prostaglandin E receptor; JNK, jun kinase; mRNA, messenger RNA; Na_v1.8/1.9, voltage gated sodium channel type 1.8/1.9; NGF, nerve growth factor; P38, serinethreonine kinase; PKA, protein kinase A; PKC, protein kinase C; TRP, transient receptor potential.

(From Woolf CJ: Pain: Moving from symptom control toward mechanism-specific pharmacologic management.Ann Intern Med 2004;140:441-451.)

Figure 2–4 Contributions of spinal cord dorsal horn neurons to pain. A. Nociceptive transmission. B. The acute phase of central sensitization. C. The late phase of central sensitization. Some alterations in gene expression are activity-driven and restricted, such as dynorphin, whereas others are widespread and produce diverse changes in function, such as induction of cyclooxygenase-2 (COX-2) in central neurons after peripheral inflammation. D. Disinhibition. AA, arachidonic acid; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionate; EP, prostaglandin E receptor; IL-1, interleukin-1; NK1, neurokinin 1; NMDA, N-methyl-D-aspartic acid; PGE2, prostaglandin E2.

(From Woolf CJ: Pain: Moving from symptom control toward mechanism-specific pharmacologic management.Ann Intern Med 2004;140:441-451.)

Figure 2–5 Scheme of the Major Signaling Pathways that Regulate TRP Ion Channels. (+) represents sensitization or activation; (−) represents desensitization. In the early phase of inflammation, increased pain sensitivity originates largely as a result of the local release from inflammatory cells of a number of mediators. Most of these inflammatory mediators do not directly activate nociceptors, but rather act as sensitizers, reducing the threshold of the peripheral nociceptor terminals. Among the major inflammatory mediators are prostanoids, particularly prostaglandin E₂ (PGE₂), bradykinin, and nerve growth factor. These chemicals acting through EP prostaglandin and B₁/B₂ bradykinin G protein-coupled receptors and the high-affinity TrkA NGF receptor produce their immediate effects on pain hypersensitivity locally on the nociceptor terminals by phosphorylating TRPV1 as well as the sensory neuron-specific voltage-gated sodium channel Nav 1.8. Activation of the protease-activated receptor 2 by inflammatory proteases like trypsin has a similar effect. Phosphorylation and dephosphorylation substantially alter TRPV1 ion channel function, and this represents a major means of rapidly and dynamically altering pain sensitivity. AA, arachidonic acid; AC, adenylate cyclase; AKAP, A-kinase anchor proteins; B₂R, bradykinin receptor 2 (BDKRB2); CaM, calmodulin; CaMKII, calmodulin dependent kinase II; COX, cyclooxygenase; DAG, diacylglycerol; EET, epoxyeicosatrienoic acids; EP, prostaglandin E; ER, endoplasmic reticulum; ERK, extracellular-signal-regulated kinases; G11, guanine nucleotide-binding (G) protein-subunits 11; HPETE, hydroperoxyeicosatetraenoic acid; IP₃R, inositol 1,4,5-trisphosphate receptor; LOX, lipooxygenase; NGF, nerve growth factor; PIP₂, phosphatidylinositol 4,5-bisphosphate; PIP₃, phosphatidylinositol (3,4,5)-trisphosphate; PI3K, phosphatidylinositol 3-kinases; PKA, protein kinase A; PKC, protein kinase C; PLA2, phospholipases A2; PLC, phospholipase C; PP2B, protein phosphatase 2B (Calcineurin (CN)); P38, mitogen-activated protein kinases; P450, cytochrome P450; Src, a family of proto-oncogenic tyrosine kinases, Rous sarcoma virus (RSV); Trk A, tyrosine kinase A; TRP, transient receptor potential (has TRPV, TRPM, TRPA, and TRPC subfamilies).

(Modified from Wang H, Woolf CJ. Pain TRPs. Neuron 2005;46:9-12.)

Figure 2–6 Effect of the presence (panel A) and absence (panel B) of downstream regulatory element antagonistic modulator (DREAM) on nociceptive processing after noxious stimulation of the skin with a pin. In panel A, the prodynorphin gene is blocked by DREAM, and the nociceptive signal is transmitted by substance P (SP)-containing dorsal root neurons essentially unaltered through the spinal cord. This activated state is characterized by a large depolarizing potential and multiple spike discharges. Such activity subsequently activates systems governing descending regulatory control and thalamic nuceli, triggering the perception of pain. In panel B, DREAM has been knocked out, and the release of dynorphin from spinal cord interneurons becomes a prominent part of the nociceptive response. This inactivates spinal-projection neurons, leading to a greatly reduced excitatory response. Subsequently, there is almost complete inactivation of descending regulatory and pain-processing systems. In addition to raising issues related to the specific functions of DREAM, this simple scheme emphasizes the importance of neurophysiological research involving this model and hypotheses to guide drug design.

(From Vogt BA. Knocking out the DREAM to study pain.N Engl J Med 2002; 347: 362-364.)

Ectopic excitability, structural reorganization, and decreased inhibition are unique to neuropathic pain, whereas peripheral sensitization occurs in inflammatory pain and in some forms of neuropathic pain.

Pain transient receptor potential (TRP) ion channels are listed in Table 2.2 and illustrated in Figure 2-6. TRP ion channels are molecular gateways in sensory systems, an interface between the environment and the nervous system. Several TRPs transduce thermal, chemical, and mechanical stimuli into inward currents, an essential first step in eliciting thermal and pain sensations.

Table 2.2 Mammalian Sensory Transient Receptor Potentials (TRPs)