OPIOID ANALGESICS

The term opioid refers broadly to all compounds related to opium, a natural product derived from

the poppy. Opiates are drugs derived from opium and include the natural products morphine,

codeine, and thebaine, and many semisynthetic derivatives. Endogenous opioid peptides, or

endorphins, are the naturally occurring ligands for opioid receptors. Opiates exert their effects by

mimicking these peptides. The term narcotic is derived from the Greek word for “stupor”; it originally

referred to any drug that induced sleep, but it now is associated with opioids.

The diverse functions of the endogenous opioid system include the best known sensory role, prominent

in inhibiting responses to painful stimuli; a modulatory role in gastrointestinal (GI), endocrine,

and autonomic functions; an emotional role, evident in the powerful rewarding and addicting properties

of opioids; and a cognitive role in the modulation of learning and memory. The endogenous opioid

system has considerable diversity in endogenous ligands (>12) but only 4 major receptor types.

ENDOGENOUS OPIOID PEPTIDES

Three distinct families of classical opioid peptides have been identified: the enkephalins, endorphins,

and dynorphins. Each family derives from a distinct precursor protein, prepro-opiomelanocortin

(POMC), preproenkephalin, and preprodynorphin, respectively, which are encoded by

distinct genes. Each precursor is subject to complex cleavages and posttranslational modifications

that result in the synthesis of multiple active peptides. The opioid peptides share a common

amino-terminal sequence of Tyr-Gly-Gly-Phe-(Met or Leu), the opioid motif. This motif is followed

by C-terminal extensions yielding peptides ranging from 5 to 31 residues (Table 21–1).

The major opioid peptide derived from POMC is b-endorphin. In addition to b-endorphin, the

POMC precursor also is processed into the nonopioid peptides adrenocorticotropic hormone

(ACTH), melanocyte-stimulating hormone (a-MSH), and b-lipotropin b-LPH). Proenkephalin

contains multiple copies of met-enkephalin, as well as a single copy of leu-enkephalin. Prodynorphin

contains three peptides of differing lengths that all begin with the leu-enkephalin sequence:

dynorphin A, dynorphin B, and neoendorphin (Figure 21–1).

A novel endogenous opioid peptide with significant sequence homology to dynorphin A was

alternatively termed nociceptin or orphanin FQ (now termed N/OFQ; Table 21–1). The substitution

of Phe for Tyr in the opioid motif is sufficient to abolish interactions with the three classical opioid

peptide receptors. N/OFQ has behavioral and pain modulatory properties distinct from those of the

three classical opioid peptides.

OPIOID RECEPTORS

Three classical opioid receptor types, m, d, and k, have been studied extensively; the N/OFQ receptor

system is still being defined. Highly selective ligands that allowed for type-specific labeling of

the three classical opioid receptors (e.g., DAMGO for m, DPDPE for d, and U-50,488 and U-69,593

for k) made possible the definition of ligand-binding characteristics of each of the receptor types

and the determination of anatomical distribution of the receptors using autoradiographic techniques.

Each major opioid receptor has a unique anatomical distribution in brain, spinal cord, and

the periphery.

Receptor-selective antagonists and agonists have aided the study of the biological functions of

opioid receptors. Commonly used antagonists are cyclic analogs of somatostatin such as CTOP as

m-receptor antagonists, a derivative of naloxone called naltrindole as a d-receptor antagonist, and

a bivalent derivative of naltrexone called nor-binaltorphimine (nor-BNI) as a k-receptor antagonist.

In general, functional studies using selective agonists and antagonists have revealed substantial parallels

between m and d receptors and dramatic contrasts between m/d and k receptors. In vivo infusions

of selective antagonists and agonists also were used to establish the receptor types involved

in mediating various opioid effects (Table 21–2).

Most of the clinically used opioids are relatively selective for m receptors, reflecting their similarity

to morphine (Tables 21–3 and 21–4). However, drugs that are relatively selective at standard

doses may interact with additional receptor subtypes when given at sufficiently high doses, leading

to possible changes in their pharmacological profile. This is especially true as doses are escalated

to overcome tolerance. Some drugs, particularly mixed agonist–antagonist agents, interact with

more than one receptor class at usual clinical doses and may act as an agonist at one receptor and

an antagonist at another.

21

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350Table 21–1

Endogenous and Synthetic Opioid Peptides

Selected Endogenous Opioid Peptides

[Leu5]enkephalin Tyr-Gly-Gly-Phe-Leu

[Met5]enkephalin Tyr-Gly-Gly-Phe-Met

Dynorphin A Tyr-Gly-Gly-Phe-Leu-Arg-Arg-IIe-Arg-Pro-Lys-Leu-Lys-Trp-

Asp-Asn-Gln

Dynorphin B Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr

a-Neoendorphin Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro-Lys

b-Neoendorphin Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro

b-Endorphin Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-

Val-Thr-Leu-Phe-Lys-Asn-Ala-Ile-Ile-Lys-Asn-Ala-Tyr-Lys-

Lys-Gly-Glu

Novel Endogenous Opioid-Related Peptides

Orphanin FQ/Nociceptin Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-

Leu-Ala-Asn-Gln

Selected Synthetic Opioid Peptides

DAMGO [D-Ala2,MePhe4,Gly(ol)5]enkephalin

DPDPE [D-Pen2,d-Pen5]enkephalin

DSLET [D-Ser2,Leu5]enkephalin-Thr6

DADL [D-Ala2,D-Leu5]enkephalin

CTOP D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2

FK-33824 [D-Ala2,N-MePhe4,Met(O)5-ol]enkephalin

[D-Ala2]Deltorphin I Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2

[D-Ala2,Glu4]Deltorphin II Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2

Morphiceptin Tyr-Pro-Phe-Pro-NH2

PL-017 Tyr-Pro-MePhe-D-Pro-NH2

DALCE [D-Ala2,Leu5,Cys6]enkephalin

FIGURE 21–1 Peptide precursors. POMC, pro-opiomelanocortin; ACTH, adrenocorticotropic hormone; b-LPH,

b-lipotropin.

CHAPTER 21 Opioid Analgesics 351

Opioid Receptor Signaling and Consequent Intracellular Events

COUPLING OF OPIOID RECEPTORS TO SECOND MESSENGERS

The m, d and k receptors are coupled, via pertussis toxin–sensitive G proteins, to inhibition of

adenylyl cyclase activity, activation of receptor-linked K+ currents, and suppression of voltagegated

Ca2+ currents. The hyperpolarization of membrane potential by K+-current activation and

the limiting of Ca2+ entry by suppression of Ca2+ currents are tenable but unproven mechanisms

for explaining opioid inhibition of neurotransmitter release and pain transmission. Opioid receptors

couple to an array of second-messenger systems, including activation of MAP kinases and the

phospholipase C (PLC)–mediated cascade. Prolonged exposure to opioids results in adaptations

at multiple levels within these signaling cascades that may relate to effects such as tolerance, sensitization,

and withdrawal.

RECEPTOR DESENSITIZATION, INTERNALIZATION, AND SEQUESTRATION AFTER

CHRONIC EXPOSURE TO OPIOIDS

Tolerance refers to a decrease in effectiveness of a drug with its repeated administration (see

Chapter 23). Transient administration of opioids leads to a phenomenon called acute tolerance,

whereas sustained administration leads to the development of classical or chronic tolerance.

Short-term receptor desensitization, which may underlie the development of tolerance, probably

involves phosphorylation of the m and d receptors by PKC. A number of other kinases have been

implicated in desensitization, including PKA and b-adrenergic receptor kinase.

Long-term tolerance may be associated with increases in adenylyl cyclase activity—a

counter-regulation to the decreased cyclic AMP levels seen after acute opioid administration.

Chronic treatment with m-receptor opioids causes superactivation of adenylyl cyclase. This

effect is prevented by pretreatment with pertussis toxin, demonstrating involvement of Gi/o proteins,

and also by cotransfection with scavengers of G protein–bg dimers, indicating a role for

this complex in superactivation. Recent data, described in the 11th edition of the parent text,

argue that opioid tolerance may be related not to receptor desensitization but rather to a lack

of desensitization.

Table 21–2

Classification of Opioid Receptor Subtypes and Actions from Animal Models

Actions of:

Receptor

Subtype Agonist Antagonist

Analgesia

Supraspinal m, k, d Analgesic No effect

Spinal m, k, d Analgesic No effect

Respiratory function m Decrease No effect

Gastrointestinal tract m, k Decrease transit No effect

Psychotomimesis k Increase No effect

Feeding m, k, d Increase feeding Decrease feeding

Sedation m, k Increase No effect

Diuresis k Increase

Hormone regulation

Prolactin m Increase release Decrease release

Growth hormone m and/or d Increase release Decrease release

Neurotransmitter release

Acetylcholine m Inhibit

Dopamine m, d Inhibit

Isolated organ bioassays

Guinea pig ileum m Decrease contraction No effect

Mouse vas deferens d Decrease contraction No effect

The actions listed for antagonists are seen with the antagonist alone. All the correlations in this table are based on studies

in rats and mice, which occasionally show species differences. Thus, any extensions of these associations to humans

are tentative. Clinical studies do indicate that m receptors elicit analgesia spinally and supraspinally. Preliminary work

with a synthetic opioid peptide, [D-Ala2,D-Leu5]enkephalin, suggests that intrathecal d agonists are analgesic in humans.