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 ³stupor´; 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, preproopiomelanocortin (POMC), preproenkephalin, and preprodynorphin, respectively, which are encoded by distinct genes. Each precursor is subject to complex cleavages and posttranslational modifications

and neoendorphin (Figure 21±1). the POMC precursor also is processed into the nonopioid peptides adrenocorticotropic hormone (ACTH). The substitution of Phe for Tyr in the opioid motif is sufficient to abolish interactions with the three classical opioid peptide receptors. and k. OPIOID RECEPTORS Three classical opioid receptor types. A novel endogenous opioid peptide with significant sequence homology to dynorphin A was alternatively termed nociceptin or orphanin FQ (now termed N/OFQ. The major opioid peptide derived from POMC is b-endorphin. In addition to b-endorphin. the N/OFQ receptor system is still being defined. Prodynorphin contains three peptides of differing lengths that all begin with the leu-enkephalin sequence: dynorphin A. d. This motif is followed by C-terminal extensions yielding peptides ranging from 5 to 31 residues (Table 21±1). contains multiple copies of met-enkephalin. N/OFQ has behavioral and pain modulatory properties distinct from those of the three classical opioid peptides. dynorphin B. melanocyte-stimulating Proenkephalin hormone (a-MSH). Highly selective ligands that allowed for type-specific labeling of . Table 21±1).that result in the synthesis of multiple active peptides. and b-lipotropin b-LPH). the opioid motif. m. have been studied extensively. The opioid peptides share a common amino-terminal sequence of Tyr-Gly-Gly-Phe-(Met or Leu). as well as a single copy of leu-enkephalin.

and the periphery. However. Receptor-selective antagonists and agonists have aided the study of the biological functions of opioid receptors. DAMGO for m. 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). Each major opioid receptor has a unique anatomical distribution in brain. and a bivalent derivative of naltrexone called nor-binaltorphimine (nor-BNI) as a k-receptor antagonist.g.488 and U-69.. drugs that are relatively selective at standard doses may interact with additional receptor subtypes when given at sufficiently high doses. In general.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. leading . a derivative of naloxone called naltrindole as a d-receptor antagonist. reflecting their similarity to morphine (Tables 21±3 and 21±4).the three classical opioid receptors (e. 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. Most of the clinically used opioids are relatively selective for m receptors. and U-50. DPDPE for d. Commonly used antagonists are cyclic analogs of somatostatin such as CTOP as m-receptor antagonists. spinal cord.

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. This is especially true as doses are escalated to overcome tolerance.to possible changes in their pharmacological profile. Inc. 21 Copyright © 2008 by The McGraw-Hill Companies. particularly mixed agonist±antagonist agents. 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-TrpAsp-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-LeuVal-Thr-Leu-Phe-Lys-Asn-Ala-Ile-Ile-Lys-Asn-Ala-Tyr-LysLys-Gly-Glu Novel Endogenous Opioid-Related Peptides Orphanin FQ/Nociceptin Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-LysLeu-Ala-Asn-Gln Selected Synthetic Opioid Peptides . Click here for terms of use. Some drugs.

Leu5]enkephalin-Thr6 DADL [D-Ala2. CHAPTER 21 Opioid Analgesics 351 Opioid Receptor Signaling and Consequent Intracellular Events COUPLING OF OPIOID RECEPTORS TO SECOND MESSENGERS The m. Opioid receptors of neurotransmitter release and pain POMC. adrenocorticotropic hormone.DAMGO [D-Ala2.d-Pen5]enkephalin DSLET [D-Ser2.Leu5.MePhe4. activation of receptor-linked K+ currents.Cys6]enkephalin FIGURE 21±1 Peptide precursors. ACTH.Met(O)5-ol]enkephalin [D-Ala2]Deltorphin I Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2 [D-Ala2.N-MePhe4. d and k receptors are coupled. and suppression of voltagegated Ca2+ currents.D-Leu5]enkephalin CTOP D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 FK-33824 [D-Ala2. to inhibition of adenylyl cyclase activity.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. b-lipotropin. b-LPH. . via pertussis toxin±sensitive G proteins.Gly(ol)5]enkephalin DPDPE [D-Pen2. pro-opiomelanocortin. 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 transmission.

probably involves phosphorylation of the m and d receptors by PKC. and withdrawal. including PKA and b-adrenergic receptor kinase. sensitization. Prolonged exposure to opioids results in adaptations at multiple levels within these signaling cascades that may relate to effects such as tolerance. demonstrating involvement of Gi/o proteins. Long-term tolerance may be associated with increases in adenylyl cyclase activity²a counter-regulation to the decreased cyclic AMP levels seen after acute opioid administration. whereas sustained administration leads to the development of classical or chronic tolerance.couple to an array of second-messenger systems. RECEPTOR AFTER DESENSITIZATION. including activation of MAP kinases and the phospholipase C (PLC)±mediated cascade. This effect is prevented by pretreatment with pertussis toxin. Short-term receptor desensitization. Transient administration of opioids leads to a phenomenon called acute tolerance. Chronic treatment with m-receptor opioids causes superactivation of adenylyl cyclase. A number of other kinases have been implicated in desensitization. which may underlie the development of tolerance. . AND SEQUESTRATION CHRONIC EXPOSURE TO OPIOIDS Tolerance refers to a decrease in effectiveness of a drug with its repeated administration (see Chapter 23). INTERNALIZATION.

Table 21±2 Classification of Opioid Receptor Subtypes and Actions from Animal Models Actions of: Receptor Subtype Agonist Antagonist Analgesia Supraspinal m. d Analgesic No effect Spinal m. k. argue that opioid tolerance may be related not to receptor desensitization but rather to a lack of desensitization. Recent data. described in the 11th edition of the parent text. d Analgesic No effect Respiratory function m Decrease No effect Gastrointestinal tract m.and also by cotransfection with scavengers of G protein±bg dimers. 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 . indicating a role for this complex in superactivation. k Decrease transit No effect Psychotomimesis k Increase No effect Feeding m. d Increase feeding Decrease feeding Sedation m. k. k.

Clinical studies do indicate that m receptors elicit analgesia spinally and supraspinally. . any extensions of these associations to humans are tentative. suggests that intrathecal d agonists are analgesic in humans. [D-Ala2.D-Leu5]enkephalin. which occasionally show species differences.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. Thus. All the correlations in this table are based on studies in rats and mice. Preliminary work with a synthetic opioid peptide.