Neurophysiology of Pain

Sensations of pain are modulated by both ascending and descending pathways in the central nervous system (CNS). Noxious or nociceptive stimuli activate highly developed endings on primary afferent neurons, termed nociceptors (pain receptors). These stimuli give rise to action potentials that are transmitted along afferent neurons into the dorsal horn of the spinal cord. A-delta (Aδ) fibers are small, myelinated, rapidly conducting afferent neurons that terminate in lamina I of the spinal cord. They have a relatively high threshold for activation by mechanical and thermal stimuli and mediate sharp and localized pain, often termed somatic pain. C-fibers are even smaller unmyelinated afferent neurons and hence are slower conducting. They are polymodal and are activated by mechanical, thermal, or chemical stimuli. They terminate in lamina II of the spinal cord (substantia gelatinosa) and mediate dull, diffuse, aching, or burning pain sometimes called visceral pain (see Chapter 13, Fig. 13-5). Aδ and C-fibers release excitatory amino acids in the dorsal horn; C-fibers, which are stimulated by bradykinin and prostaglandins (PGs) released from local damaged cells, release substance P and other neuropeptides. These neurotransmitters activate secondary neurons that form the ascending spinothalamic pathway, which projects to supraspinal nuclei in the thalamus and then to the limbic system and cerebral cortex (Fig. 36-1, A).

FIGURE 36–1 A, Ascending spinothalamic tract pain-transmitting pathway and descending pain-inhibitory pathway originating in the midbrain. B, Possible synaptic connections in the dorsal horn and mediators that may influence the transmission of pain stimuli.

Descending pain-inhibitory systems originate in the periaqueductal gray region of the midbrain and from several nuclei of the rostroventral medulla oblongata and project downward to the dorsal horn. These descending systems release norepinephrine (NE), 5-HT, and other neurotransmitters and thereby inhibit the activity of the ascending pain pathways, either through direct synaptic contacts or indirectly by activating inhibitory interneurons. These pathways are illustrated in Figure 36-1, B.

Opioids

Three major families of opioid peptides have been identified: the enkephalins, endorphins, and dynorphins. They are derived from precursor molecules encoded by separate genes—proenkephalin, proopiomelanocortin, and prodynorphin, respectively. Although found primarily in the CNS, some opioid peptides, notably the enkephalins, also exist in peripheral tissues such as nerve plexuses of the gastrointestinal (GI) tract and the adrenal medulla (Table 36-1).

TABLE 36–1 Principal Endogenous Opioid Peptides

Enkephalinergic interneurons in the dorsal horn produce presynaptic inhibition of primary afferent neurons and postsynaptic inhibition of secondary neurons in ascending pathways. Shorter-chain products of prodynorphin, notably dynorphin A (1-8), like the enkephalins, occur in interneurons distributed widely throughout the CNS and are prevalent in laminae I and II of the spinal cord.

β-Endorphin and longer-chain dynorphins, such as dynorphin A (1-17), have a more limited distribution in the CNS and may not influence pain processing directly. Rather, they may have hormonal roles in responses to stress and fluid homeostasis, respectively. The structures of the three classical families of opioid peptides are shown in Figure 36-2.

FIGURE 36–2 The major families of opioid peptides—endorphins, enkephalins, dynorphins—are derived from distinct precursor molecules—proopiomelanocortin, proenkephalin A, prodynorphin—and are encoded by three distinct genes.

Three major opioid receptors have been identified by pharmacological means and molecular cloning and are designated μ, κ, and δ (Table 36-2). They are also referred to by either their International Union of Pharmacology nomenclature (OP₃, OP₂, and OP₁, respectively) or their molecular biological nomenclature (MOP, KOP, and DOP, respectively). All three receptors belong to the superfamily of G-protein-coupled receptors with the characteristic seven transmembrane-spanning regions (see Chapter 1). Activation of these receptors decreases synthesis of cyclic adenosine monophosphate, increases K⁺ conductance, and decreases Ca⁺⁺ conductance, effects illustrated in Figure 36-3. Because changes in K⁺ and Ca⁺⁺ conductances inhibit neuronal activity, activation of any of the three opioid receptors usually results in decreased neuronal transmission.

TABLE 36–2 Opioid Receptors and their Ligands

FIGURE 36–3 Mechanism of action of opioids on neurons. Opioid receptors μ, δ, and κ are coupled negatively to adenylyl cyclase (AC) by G-proteins (G_i). Activation of an opioid receptor by an agonist decreases activity of adenylyl cyclase, resulting in a decrease in the production of cyclic adenosine monophosphate (cAMP). This leads to an increase in the efflux of K⁺ and cellular hyperpolarization and a decrease in the influx of Ca⁺⁺ and lower intracellular concentrations of free Ca⁺⁺. The overall consequence is a decrease in the neuronal release of neurotransmitters. Opioid receptors also may be coupled by G-proteins to intracellular second messengers other than cAMP.

The selectivity of opioid receptors for endogenous and drug ligands is shown in Table 36-2. The anatomical distribution of opioid receptors is consistent with the actions of the opioids—that is, they are found prominently among structures of the ascending and descending pain-modulatory pathways. All clinically important effects of morphine and morphine-like drugs are mediated by μ receptors. Some of the effects of mixed-action opioids, including analgesia at the level of the spinal cord, sedation, and the dysphoria that occurs at high doses, are mediated by κ receptors. With the exception of the opioid antagonists, there are currently no therapeutic agents that interact with μ receptors in a clinically meaningful way. In cases in which opioids can be resolved into optical isomers, the levorotatory isomer usually has a considerably higher affinity for opioid receptors than does its dextrorotatory counterpart. The structures of morphine and representative agonist/antagonist compounds are shown in Figure 36-4.

FIGURE 36–4 Structures of morphine and representative partial-agonist, agonist-antagonist, and antagonist opioid drugs.

NSAIDs and Acetaminophen

The mechanism of action, all of the therapeutic effects, and many of the side effects of the NSAIDs are due to inhibition of cyclooxygenase (COX), an enzyme involved in the metabolism of the eicosanoids. The eicosanoids are derivatives of arachidonic acid and include the leukotrienes synthesized by the action of 5-lipoxygenases, and the PGs and thromboxanes (TXs) synthesized by the action of the COXs (see Chapter 15, Fig. 15-1). Two distinct COX enzymes have been identified. COX-1 is constitutively expressed and is involved in “housekeeping tasks” in cells. COX-2 occurs constitutively in some tissues but is largely inducible, and induction results in a marked increase in the rate of synthesis and release of COX products, particularly the PGs. Aspirin acetylates both COX enzymes, inhibiting their activity irreversibly, whereas other nonselective NSAIDs inhibit the COX enzymes reversibly. The COX-2 inhibitors are 8- to 35-fold more selective for COX-2 relative to COX-1 and inhibit COX-2 irreversibly in a time-dependent manner. The functional consequences of inhibition of COX-2 relative to COX-1 are depicted in Figure 36-5. Structures of aspirin, acetaminophen, and the COX-2 inhibitor celecoxib are shown in Figure 36-6.

FIGURE 36–5 NSAIDs produce their therapeutic effects and many side effects by inhibiting the cyclooxygenase (COX) enzymes. Drugs that inhibit COX-2 selectively may produce fewer adverse side effects than do those that inhibit both isoforms of the enzyme.

FIGURE 36–6 Structures of aspirin, acetaminophen, and celecoxib.

At the site of injury, PGs sensitize nociceptors to many chemical mediators of pain, including bradykinin, cytokines, and certain amino acids and neuropeptides, and to mechanical and thermal stimuli. In addition, PGs and prostacyclin (PGI₂) promote blood flow to injured tissues, resulting in leukocyte infiltration. These effects, together with leukotriene-induced increases in vascular permeability and attraction of polymorphonuclear leukocytes, lead to edema and inflammation. Peripheral inflammation also is associated with an increased expression of COX-2 in the dorsal horn of the spinal cord. Viruses and bacterial endotoxins, through a chain of events, induce COX-2 in the preoptic nuclei of the hypothalamus, the thermoregulatory center of the body. Prostaglandin E₂, in particular, is a potent pyrogen that raises the set-point of the thermoregulatory center, resulting in elevated body temperature. Thus inhibition of COX-2 can be an effective treatment for certain types of pain, inflammation, and fever.

Drugs for Specific Pain Syndromes

Gout

As mentioned, gout is an inflammatory disease caused by increased uric acid in the blood and the deposition of uric acid crystals in bone joints. Uric acid is a waste product formed from the catabolism of purines and normally dissolves in blood and is excreted by the kidneys. However, if too much uric acid is formed or too little is excreted, urate crystals precipitate. Crystals in the joints and surrounding tissue attract leukocytes, which attempt to phagocytose them, releasing inflammatory mediators in the process. In classical acute gout, the big toe is the body part most often the site of the inflammatory response and associated pain. Gout occurs in approximately 0.6% of men and 0.1% of women, primarily after menopause.

Drugs from several pharmacological classes are used to treat or prevent gout. The NSAIDs and the corticosteroids (see Chapter 39) attenuate inflammatory responses to urate crystals and the associated pain. Colchicine also reduces the inflammatory response, but through a different mechanism. Colchicine binds to tubulin in leukocytes, causing microtubules to disaggregate. This affects the structure of the cells, inhibiting their migration into the inflamed area and reducing phagocytic activity.

Specific drugs are used to correct the underlying hyperuricemia in gout. Allopurinol, a structural analog of the purine hypoxanthine, inhibits the enzyme xanthine oxidase (Fig. 36-7), blocking the metabolism of hypoxanthine and xanthine to uric acid and lowering blood urate concentrations. Normally, approximately 90% of filtered urate is resorbed and only 10% is excreted. The uricosuric agents probenecid and sulfinpyrazone increase urate excretion by competing with uric acid for the renal tubular acid transporter so less urate is resorbed.

FIGURE 36–7 Blockade of uric acid synthesis by allopurinol and its oxidated metabolite, oxypurinol.

Opioids

Many opioids are administered parenterally, even though they are well absorbed from the GI tract. However, some opioids, such as morphine and the antagonist naloxone, undergo extensive first-pass metabolism in the liver, greatly reducing their bioavailability and therapeutic efficacy after oral administration. Although morphine often is administered orally for management of chronic pain, oral administration is much less potent compared with parenteral administration. Drugs with greater lipophilicity, including fentanyl and buprenorphine, are well absorbed through the nasal and buccal mucosa. The most lipophilic of opioids, including fentanyl, are absorbed transdermally as well. Serum protein binding ranges from approximately 30% for morphine to 80% to 90% for fentanyl and its derivatives. The pharmacokinetic profile of an opioid is a major determinant of its therapeutic use.

Because of their physicochemical properties, the speed of onset and duration of action of opioids do not always correlate with their plasma concentrations or elimination half-lives. For example, the rise in plasma concentrations of morphine long precedes the onset of analgesia because this hydrophilic drug penetrates the blood-brain barrier very slowly. In contrast, plasma concentrations of fentanyl closely parallel its therapeutic effect. Because of the rapid redistribution of lipophilic fentanyl from brain to lean body mass, its short duration of action is not predictable from its elimination half-life, which exceeds that of the longer-acting morphine. Opioids with relatively long elimination half-lives can accumulate in the body upon repeated dosing, thereby prolonging their duration of action. Remifentanil, a fentanyl analog ester, is so rapidly metabolized by plasma esterases that its plasma half-life is only 10 to 20 minutes. It does not accumulate upon repeated or slow continuous administration.

Opioids are metabolized mainly in the liver, usually to more polar and less active or inactive compounds. The mechanisms involved include N-dealkylation, conjugation of hydroxyl groups, and hydrolysis. However, metabolites account for most of the opioid activity of codeine (3-methoxymorphine) and its analogs, heroin (diacetylmorphine) and tramadol, which have weak affinity for the μ opioid receptor and have little activity themselves. The two hydroxyl groups of morphine are conjugated with glucuronic acid to produce two metabolites. Morphine-3-glucuronide is inactive, but morphine-6-glucuronide has a higher affinity for the μ opioid receptor and is a more potent analgesic than morphine. Morphine-6-glucuronide accumulates during long-term morphine treatment, and measurable amounts are found in cerebrospinal fluid. However, morphine-6-glucuronide is relatively polar and penetrates the blood-brain barrier poorly. Thus the extent to which it contributes to the analgesic effect of morphine administered acutely is unknown.

The accumulation of normeperidine, the N

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