Ch 23-Opioid Analgesics PDF

23 Chapter INTRODUCTION TO OPIOIDS AND RECEPTORS OPIOID RECEPTORS Opioid Analgesics Emily M. Jutkiewicz and John R. Traynor...

23 Chapter INTRODUCTION TO OPIOIDS AND RECEPTORS OPIOID RECEPTORS Opioid Analgesics Emily M. Jutkiewicz and John R. Traynor Oxymorphone, Oxycodone, and Hydrocodone Morphinans Piperidine and Phenylpiperidine Analgesics Types of Opioid Receptors Fentanyl and Its Analogues Opioid Receptor Distribution Methadone Opioid Receptor Signaling Partial Agonists Opioid Receptor Ligands Other Opioid Agonists Opioid Receptor Structure and Activation DOSAGE AND ROUTES OF OPIOID ANALGESIC PHARMACOLOGY OF CLINICALLY EMPLOYED ADMINISTRATION OPIOID DRUGS Opioid Rotation Pharmacology of the Prototypical Mu-Opioid Agonist Morphine Combination Therapy CHRONIC EFFECTS OF MU-OPIOID DRUGS: TOLERANCE, OPIOID ANTAGONISTS DEPENDENCE, AND OPIOID USE DISORDER Therapeutic Uses Pharmacological Properties Tolerance ADME Dependence Opioid Use Disorder ACUTE OPIOID TOXICITY Mechanisms of Tolerance, Dependence, Withdrawal, and Abuse Liability Adverse Effects and Precautions Affecting Patient Responses to ADDITIONAL THERAPEUTIC USES OF OPIOIDS Mu-Opioids Dyspnea MORPHINE AND STRUCTURALLY RELATED AGONISTS Anesthetic Adjuvants Chemistry and Structure-Activity Relationships OPIOID-RELATED ANTITUSSIVE AGENTS Morphine Codeine OVERALL SUMMARY AND CONCLUSIONS Heroin Hydromorphone somniferum. Opium also contains thebaine, which has no opioid activity Introduction to Opioids and Receptors but serves as a precursor for the synthesis of additional opioid drugs. Also Pain is a common component of many clinical pathologies, and manage- present in opium are papaverine (1%), a smooth muscle relaxant, and ment of pain is a vital clinical need. Drugs such as morphine and oxyco- noscapine (6%), which has been used as an antitussive. Morphine, codeine, done acting at opioid receptors remain the mainstay of pain treatment, and structurally related compounds found in opium, together with despite the safety concerns associated with the long-term use of these semisynthetic derivatives such as oxycodone that bind to the mu-opioid drugs, which has led to addiction and death from their misuse and the receptor, are termed opiates. In contrast, an opioid is any agent that binds worldwide opioid crisis. Morphine and related drugs exert their phar- to the ligand-binding (orthosteric) site of members of the opioid receptor macological effects by acting at opioid receptors. Opioid receptors are family. Consequently, the term opioid is a broader definition and cov- 7-transmembrane G protein-coupled receptors (GPCRs; see Chapter 3) ers the opiates, fully synthetic drugs, such a methadone and fentanyl, and and comprise a family of four types, the mu (μ), delta (δ), kappa (κ) opi- endogenous opioid peptides, including the enkephalins, endorphins, and oid receptors, which we will refer to as the classical or canonical opioid dynorphins, which are the naturally occurring neurotransmitters acting receptors, and the nociceptin (NOP) receptor (NOPr), which has close at opioid receptors. Opioid drugs are often referred to as narcotic analge- structural homology to the classical opioid receptors but distinct lig- sics or narcotics, derived from the Greek word narkotikos for “benumb- ands and pharmacology. In this chapter, we will use mu, delta, kappa, ing” or “stupor,” because of their sedative properties and ability to cause and NOPr to describe the receptors. The mu-opioid receptor is mainly sleep in the presence of pain. responsible for the pain-relieving actions and, importantly, also the unwanted effects, of all clinically useful opioid analgesics, which gener- ally mimic the pharmacology of morphine. Consequently, this chapter Opioid Receptors will focus mainly on this receptor and its ligands and their pharmacol- ogy, with some mention of the pharmacology of drugs acting at the delta, Types of Opioid Receptors kappa, and NOPr receptors. The three types of classical opioid receptors, mu, delta, and kappa, share The original opioid drugs (morphine and codeine) are components of extensive sequence homology (55%–58%) and belong to the class A or opium, the dried resin from the seed head of the opium poppy, Papaver rhodopsin family of GPCRs (see Figures 3–14 and 23–1). As such they https://ebooksmedicine.net/  444 Abbreviations caudate-putamen, nucleus accumbens, amygdala, hypothalamus, and pituitary. Kappa-opioid receptors are also found in the found in the PAG, raphe nuclei, pons and medulla, and dorsal horn of the spinal cord, but AC: adenylyl cyclase there is very little expression in the cortex. ACTH: corticotropin; formerly adrenocorticotropic hormone Delta-opioid receptors are expressed in regions related to olfactory areas ADH: antidiuretic hormone of the brain as well as the neocortex, caudate-putamen, nucleus accumbens, COPD: chronic obstructive pulmonary disease and amygdala. There are low levels in the dorsal horn of the spinal cord. The CSF: cerebrospinal fluid delta-opioid receptor is involved in modulation of pain and mood. CYP: cytochrome P450 NOPr receptors are the most widely distributed of the opioid receptors. DAMGO: [d-Ala2,MePhe4,Gly(ol)5]enkephalin The receptor is found in most regions of the brain and spinal cord, in areas related to the physiological actions of this system in the modulation EEG: electroencephalogram of pain and reward as well as anxiety and stress, memory, and feeding FSH: follicle-stimulating hormone behaviors (Ozawa et al., 2015). CHAPTER 23 OPIOID ANALGESICS GABA: γ-aminobutyric acid Opioid receptors are also present on a variety of nonneuronal cells, GI: gastrointestinal including macrophages (peripheral and central microglia) and astrocytes GPCR: G protein-coupled receptor (Dannals, 2013; Yaksh, 1987) and in the enteric nervous system of the GRK: GPCR kinase gastrointestinal (GI) tract (Galligan and Akbarali, 2014). Delta-opioid HPA: hypothalamic-pituitary-adrenal receptors in the heart may afford cardioprotection. 5HT: serotonin LH: luteinizing hormone 6-MAM: 6-monoacetylmorphine Opioid Receptor Signaling MAO: monoamine oxidase Following agonist occupation of opioid receptors and subsequent acti- MAPK: mitogen-activated protein kinase vation of heterotrimeric G proteins, both the α subunits and βγ dimers NE: norepinephrine bind to downstream proteins to provide a complex pattern of intracellular NMDA: N-methyl-d-aspartate signals (Figure 23–2). Signaling is similar for all members of the opioid NOP: nociceptin/orphanin FQ (N/OFQ) receptor family (Al-Hasani and Bruchas, 2011). NOPr: NOP receptor The ai subunits directly inhibit the enzyme adenylyl cyclase (AC) to NSAID: nonsteroidal anti-inflammatory drug reduce levels of cyclic AMP and so inhibit the phosphorylation of many PAG: periaqueductal gray proteins that are controlled by protein kinase A–dependent regulation as PCA: patient-controlled analgesia well as cyclic AMP–dependent calcium influx. Chronic treatment with PKC: protein kinase C opioid agonists leads to a loss of responsiveness of AC and an “over- shoot” of cycle AMP production when the opioid is removed. The βγ POMC: proopiomelanocortin dimer inhibits voltage-gated Ca2+ channels on presynaptic terminals, TM: transmembrane leading to reduced Ca2+ influx and an inhibition of transmitter release (Weiss and Zamponi, 2021). For example, inhibition of γ-aminobutyric acid (GABA) release in the ventrolateral periaqueductal gray leads to activation of descending antinociceptive pathways and, in the ventral transduce agonist responses into the cell via members of the Gi/o and tegmental area, enhances dopamine release in the nucleus accumbens, Gz families of heterotrimeric G proteins. NOPr was added to the opioid an important component of the reward pathway. The βγ dimers also receptor family based on its close sequence homology (48%–49%). How- act to open K+ channels, including G protein-coupled inwardly rectify- ever, neither opioid drugs nor the enkephalins, endorphins, or dynorphin ing potassium (GIRK) channels, which leads to hyperpolarization and bind to this receptor, and agonists for the NOPr do not exhibit the same reduced neuronal firing. Both effects are important for analgesic actions pharmacology as the opioids. A previous definition of opioid receptors of the opioid drugs. The release of βγ subunits also lead to activation of required that they be sensitive to the specific opioid antagonist naloxone, the mitogen-activated protein kinase (MAPK) cascades, a diverse family but with the addition of the NOPr to this family, this is no longer the case. of kinases that modulate many cellular responses by phosphorylation, The opioid receptors appear early in vertebrate evolution (Stevens, 2009). including cell differentiation, ion channel function, and scaffolding of The gene for the human mu-opioid receptor (OPRM1) has been mapped intracellular proteins. Other enzymes such as protein kinase C (PKC) to chromosome 6, for the delta-opioid receptor (OPRD1) to chromosome and phospholipase C can be activated by βγ subunits. An important role 1, for the kappa-opioid receptor (OPRK1) to chromosome 8, and for the for βγ dimers is the recruitment of G protein receptor kinases (GRKs), NOPr (OPRL1) to chromosome 20 (Dreborg et al., 2009). specifically GRK2 and 3, to phosphorylate the receptor. This is an initial step in receptor desensitization and leads to the recruitment of β-arrestin Opioid Receptor Distribution necessary for receptor internalization prior to degradation or as a prereq- uisite for recycling of refreshed receptors to the cell membrane to receive As defined by the distribution of receptor protein, message, ligand bind- another signal. The receptor can be phosphorylated by members of the ing, and the pharmacological effects initiated by opioids, opioid recep- GRK family that do not require recruitment by the βγ or by PKC. How- tors are widely distributed in the periphery and central nervous system ever, β-arrestin also functions to scaffold and activate MAPK pathways. (Mansour et al., 1988) and are found both pre- and/or postsynaptically. Mu-opioid receptors are found in regions of the brain involved in the control of both the sensory and affective components of pain as well Opioid Receptor Ligands as modulation of many other behaviors. This includes both superficial Endogenous Opioid Peptides and deeper layers of the neocortex, caudate-putamen, nucleus accum- There are three families of endogenous opioid peptides, the enkeph- bens, ventral tegmental area, thalamus, hippocampus, amygdala, raphe alins, endorphins (principally β-endorphin), and dynorphins, which nucleus, periaqueductal gray (PAG), medulla and pons, and dorsal horn act at the classical opioid receptors. These peptides share the common of the spinal cord. amino-terminal sequence of Tyr-Gly-Gly-Phe-(Met or Leu), which The distribution of kappa-opioid receptors is consistent with the may be followed by various C-terminal extensions (Table 23–1). Thus, roles of the kappa-opioid system in regulation of diuresis, food intake, Leu- and Met-enkephalin are simple pentapeptides, whereas extended pain perception, and neuroendocrine functioning, including response forms of these, as well as the dynorphins, contain up to 17 amino acids, to stress. Major regions expressing kappa-opioid receptors are the and the endorphins are up to 31 amino acid residues in length. There  N-term M D S S A A P T N A S N C T D A L A Y 445 S G G L D T R N P G C P D S L N G D L H S L N VWS G P S P A P S C S DR S L C ECL2 P P G S I DCT T Q R L G T Y S F ECL1 K ECL3 P S T S TWP F T H T I P E M G G A P V T SECTION II T I L M I T F M W T A L F T A Y L M W Y K Q I T I S V N I K C L P V N E V I I S V T M Q V G L Y W L A P F S I A I K L H I F H S Y T L Y D I L S S C I P I I C V I T S Y I F V W T L A V V C A L A F M N C N W F I I V C T Y G F A NEUROPHARMACOLOGY L G A D I S T I N V I V F N G F A L F I P M V A C S N L T K L V V L L F F N C L N A I I L V P N M V Y I M T T P R T M V L V V Y N I V S C V T R A Y I T D G Y I L F R V T A Y R M L R R Y A I I N L D F F F R L D R C V T K H E K R C K L K K V S N R E I K E M P A R C S ICL1 V L RM L S G P K D T F ICL3 S S ICL2 N E I C-term P L P A T E A E L N E L Q H N T R D V T N A T S P H D R T N Q R I R T S N QQ = Phosphorylation site C = S-S bonding site D = Essential Aspartate = Palmitoylation site = “DRY” motif = Asparagine40 Figure 23–1 General structure of an opioid receptor. This diagram is of the mu-opioid receptor, but other opioid receptors have the same general structure and the typical characteristics of a G protein-coupled receptor (GPCR). Along the external amino terminus there are several aspartate (N) residues that are potential glycosylation sites. There are seven transmembrane (TM) regions joined by intracellular and extracellular loops (ICL and ECL, respectively), a long intracellular carboxy tail, and tyrosine (Y) and serine (S) phosphorylation sites in the areas where arrestins interact. There is a conserved aspartate (D) for binding to the terti- ary N atom found in all opioid drugs and a disulfide linkage between two cysteine residues. The Na+ binding site is in the TM bundle just below the orthosteric site. is some specificity of the peptides for the different opioid receptors, but converted to this peptide. Preproenkephalin contains the sequences for one because of this structural similarity, there is a considerable degree of over- copy of Leu-enkephalin and four copies of Met-enkephalin. Preprodynor- lap. β-Endorphin is mu-opioid receptor preferring, and the dynorphins phin contains three dynorphin peptides of differing lengths that all begin are considered the endogenous ligands for the kappa-opioid receptor. The with the Leu-enkephalin sequence: dynorphin A, dynorphin B, and neoen- simpler enkephalins are less selective for delta > mu receptors but do not dorphin. Prepronociceptin contains the sequence of the 17-amino acid pep- bind to or activate the kappa-opioid receptor. None of these ligands bind tide nociceptin (also known as orphanin FQ or N/OFQ). to NOPr. Nociceptin (a 17-amino acid peptide), also known as orpha- Not all cells that express a given opioid prohormone precursor store and nin F/Q or N/OFQ, which has an N-terminal amino acid sequence of release the same mixture of opioid peptides. This results from differential Phe-Gly-Gly-Phe, is the endogenous ligand for NOPr, and has no activity posttranslational processing of the prohormones into peptides of different at the classical opioid receptors (Lambert, 2008). The endomorphins are lengths or even breakdown of larger opioid peptides into smaller fragments; two opioid peptides with high affinity and selectivity for the mu-opioid for example, dynorphins contain the Leu-enkephalin sequence. Moreover, receptor. Although originally discovered in mammalian brain tissues, the processing can be altered in response to physiological demands, leading to precursor peptides for these have never been identified, and the origin of the release of a different mix of posttranslationally derived peptides. the endomorphins remains unknown. It is therefore up for debate as to Opioid peptides are present in areas of the central nervous system whether these are truly endogenous opioids. In total, there are more than (CNS) related to the processing of pain information (e.g., spinal cord 20 opioid peptides acting at the four opioid receptors. dorsal horn, the spinal trigeminal nucleus, and the PAG), to the modula- The opioid peptides are derived from their large precursor proteins by tion of affective behavior (e.g., amygdala, hippocampus, locus coeruleus, complex cleavage with distinct trypsin-like enzymes (Figure 23–3). Pre- and frontal cerebral cortex), to the modulation of motor control (e.g., proopiomelanocortin (pre-POMC) provides POMC, which contains the caudate nucleus and globus pallidus), to the regulation of the autonomic sequence for β-endorphin. In addition, the POMC sequence is also processed nervous system (e.g., medulla), and to neuroendocrinological functions into a variety of nonopioid peptides, including adrencorticotropin (ACTH), (e.g., median eminence). Opioid peptides are found in the plasma, and α-melanocyte-stimulating hormone, and β-lipotropin. Although β-endorphin this reflects release from secretory systems such as the pituitary, adrenals, https://ebooksmedicine.net/ contains the sequence for Met-enkephalin at its amino terminus, it is not and exocrine glands of the stomach and intestine.  446 A A MOR MOR MOR MOR MOR TRANDUCERS αi/o/z αi/o/z P P αi/o/z β γ 1 Agonis β γ 2 G-protein P 3 Ar P β γ Agonistt Agonist -p prot rotein ein P Arrestin recruitment, crui ruitme tment, nt, P binding ctivation activation sig nd signaling and internalization 4 Recycling GDP GTP GRK Ras PKC Erk1/2 JNK EFFECTORS Rho JNK CHAPTER 23 OPIOID ANALGESICS AC VGCC GIRK degradation Erk1/2 PLC MOR ATP cAMP Figure 23–2 Simplified scheme of opioid receptor signaling. In the presence of an opioid agonist (green circle), inactive receptor (red, Ri) is converted to active receptor (blue, Ra) (Step 1). This causes the α subunit of the G protein heterotrimer to exchange GDP for GTP which leads to dissociation of the α and βγ subunits that go on to modulate various downstream effectors, including kinases (e.g., PKC, ERK, and JNK [c-Jun N-terminal kinase]), small GTPases (Ras and Rho), phospholipase C (PLC), ion channels (voltage-gated calcium channels [VGCC] and G protein-coupled K+ channels [GIRKs]), enzymes, and their secondary messengers (step 2). Signaling is terminated by phosphorylation of the receptor by G protein receptor kinases (GRK), followed by arrestin recruitment, and inter- nalization (step 3). In addition, arrestins can scaffold signaling pathways. Finally, internalized receptor (green) is targeted for either degradation or recycling to the plasma membrane (step 4). MOR, mu-opioid receptor. Exogenous Opioid Receptor Ligands Antagonists. These drugs are competitive antagonists and prevent the Opioid receptor ligands are defined by their selectivity (or otherwise) for binding of opioids to the orthosteric site on opioid receptors. They have a particular opioid receptor and their functional properties as agonists, no activity themselves, but their pharmacology derives solely from block- partial agonists, antagonists, biased agonists, or allosteric modulators, as ing the actions of opioid agonists. Commonly used opioid antagonists are defined below. naloxone and naltrexone. These compounds bind to all classical opioid Agonists. Agonists bind to the orthosteric site to activate the recep- receptors with similar affinity, although as mentioned above, they do not tors, leading to modulation of a wide variety of cell signaling cascades bind to the NOPr. and resultant effects on physiology. Since clinically used drugs may Antagonists for specific opioid receptors have been developed for have varying degrees of activity at other opioid receptors, highly selec- research purposes. These include peptides, such as the somatostatin ana- tive agonists have been developed. For the classical opioid receptors, logue CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2) as a mu- these are derivatives of the endogenous opioid peptides, DAMGO opioid receptor antagonist and a derivative of enkephalin (ICI-174864) and DPDPE, for mu- and delta-opioid receptors, respectively, and as a selective delta-opioid receptor antagonist. In addition, chemical dynorphin itself for the kappa-opioid receptor (see Table 23–1). Selec- manipulation of naltrexone and its derivatives has given rise to the selec- tive small-molecule agonists are also useful as tools for preclinical in tive mu-opioid receptor antagonist cyprodime, the selective delta-opioid vivo research. These include morphine for mu-, SNC80 for delta-, and receptor antagonist naltrindole, and the selective kappa-opioid receptor U69593 and its derivatives for kappa-opioid receptors. Nociceptin itself antagonist nor-BNI (see Figure 23–4). JD-Tic is also a commonly used and the small-molecule Ro64-6198 are used as selective agonists for the and highly selective antagonist at the kappa-opioid receptor. NOPr (Figure 23–4). Inverse Agonists. The opioid receptors, like other membrane-bound Partial Agonists. Partial agonists also bind to the orthosteric site of GPCRs, are not static structures but continually move through a series of receptors but are not capable of eliciting the same level of response as seen conformations, including conformations that are able to activate intracel- with full agonists, even with escalating doses (i.e., these drugs have reduced lular signaling pathways. This gives the receptors a basal level of activity, level of efficacy or “ceiling” to the magnitude of their action). However, in the absence of an agonist, and the receptors are said to be constitutively this definition is system dependent. For example, in preclinical pain mod- active. Inverse agonists are compounds that stabilize receptors in inac- els in rodents where the nociceptive insult can be varied in intensity, even tive conformations and so inhibit constitutive activity (see Chapter 3). morphine can be observed to be a partial agonist, compared to, for exam- Of the opioid receptors, the delta-opioid receptor shows high constitutive ple, fentanyl. Similarly, buprenorphine acts as partial agonist at the mu- activity in cellular models. The selective delta-opioid receptor antagonist opioid receptor in preclinical models, but in the pain clinic, it is effective ICI-174864 also inhibits constitutive activity of the receptor and therefore in managing postoperative pain. However, the partial agonist nature of is more accurately defined as an inverse agonist. buprenorphine does mean it has a ceiling effect and so inhibits respiration Biased Agonists. Intracellular signaling downstream of opioid recep- (a dangerous side effect of opioid full agonists) to a lesser extent than mor- tors is highly complex (see Figure 23–2). Most agonists activate all of phine or oxycodone and thus may be a safer alternative. Partial agonists used these downstream pathways equally. However, biased agonists are com- in the clinic are not selective for specific opioid receptors. For example, pounds that preferentially activate a particular pathway or pathways over buprenorphine acts at all opioid receptors, including weak agonist activ- other pathways. The most observed bias is between agonists that activate ity at NOPr, and pentazocine is a partial agonist at both mu- and kappa- pathways downstream of G proteins as opposed to those downstream of opioid receptors. Partial agonists are sometimes termed agonist-antagonists β-arrestin. This became a hot area of research in opioid pharmacology because they have agonist actions but also antagonize the effects of opioid following preclinical experiments that showed β-arrestin pathways might agonists that have higher efficacy, such as hydromorphone. As such, partial be responsible for certain unwanted effects of opioid agonists, particu- agonists can precipitate withdrawal in opioid-dependent patients. larly constipation and respiratory depression, while G protein pathways  TABLE 23–1 MAJOR ENDOGENOUS OPIOID PEPTIDES Opioid Receptor Structure and Activation 447 AND DERIVATIVES The opioid receptors belong to the family of class A GPCRs (see Chapter 3) and comprise an extracellular N-terminus, seven transmembrane (TM) RECEPTOR alpha-helical structures joined by two extracellular loops and three intra- PEPTIDE STRUCTUREa PREFERENCE cellular loops and an intracellular C-terminal domain (see Figure 23–1). Classical opioid Tyr-Gly-Gly-Phe-X Two conserved cysteine residues in the first and second extracellular peptides loops form a disulfide bridge to stabilize ECL2. The extracellular loops are also N-glycosylated, which regulates export of newly synthesized X= receptors to the cell surface as well as internalization and degradation. Leu-Enkephalin Leu delta > mu These loops may also occlude access of ligands to the orthosteric binding Met-Enkephalin Met delta > mu site, thus altering ligand affinity. A short proximal section of the C-terminus is attached to the membrane by a palmitoyl group and forms an addi- SECTION II Met-Enkephalin- Met-Arg-Phe delta = mu tional small alpha-helix. The intracellular loops and C-terminus interact Arg-Phe with signaling partners within the cell membrane and inside the cell, β-Endorphin Met-Thr-Ser-Glu-Lys- mu > delta in particular G proteins and β-arrestins, and also serve as substrates for Ser-Gln-Thr-Pro-Leu- phosphorylation by GRKs and other kinases, which is an important com- Val-Thr-Leu-Phe-Lys- ponent of signal termination. Asn-Ala-Ile-Ile-Lys- The structure of all four opioid receptor types has been solved using Asn-Ala-Tyr-Lys-Lys- either X-ray crystallographic or single-particle cryogenic electron micros- NEUROPHARMACOLOGY Gly-Glu copy methods, although less information is available about the loops and α-Neoendorphin Leu-Arg-Lys-Tyr-Pro-Lys mu > delta C-terminus because of the flexibility of these regions. The amino acid resi- dues making up the TM domains, which contain the orthosteric binding site, Dynorphin 1-17 Leu-Arg-Arg-IIe-Arg- kappa are similar across all of the receptors, although NOPr is more distant from Pro-Lys-Leu-Lys-Trp- the classical opioid receptors. The opioid receptor agonists and endogenous Asp-Asn-Gln opioid peptides bind similarly in the orthosteric site of opioid receptors. For Dynorphin B Leu-Arg-Arg-Gln-Phe-Lys- kappa example, at the mu-opioid receptor the nitrogen atom and phenolic OH Val-Val-Thr in morphine-like molecules or in the Tyr moiety of the endogenous opi- Endomorphins Tyr-Pro-X-Phe-NH2 oid peptides, form a salt bridge with a negatively charged aspartate residue in TM3 that is conserved across GPCRs, and a water-mediated interaction X= with a histidine in TM6, respectively. These same residues are involved with Endomorphin 1 Trp mu ligands binding to the delta- and kappa-opioid receptors. Synthetic opioids Endomorphin 2 Phe mu that are not based on the enkephalin or morphine structure, for example, methadone and fentanyl, bind in the same orthosteric site but with different Nociceptin b Phe-Phe-Gly-Thr- NOPr interactions between the ligand and the receptors. In addition, the larger Gly-Ala-Arg-Lys-Ser-Ala- endogenous peptides extend out of the orthosteric pocket toward the extra- Arg-Lys-Leu-Ala-Asn-Gln cellular domains; these additional interactions determine the selectivity Synthetic receptor of the peptides. For example, the kappa-opioid receptor selective peptide selective peptidesc dynorphin has several basic arginine residues that interact with negatively DAMGO Tyr-D-Ala-Gly-MePhe-Gly-ol charged residues on the N-terminus of the kappa receptor but are absent on the N-terminus of the other opioid receptors. DPDPE Tyr-D-Pen-Gly-Phe-Pen Opioid receptors, like all GPCRs, are flexible proteins that exist in S′ S′ multiple conformational states, but in the simplest model, there is DPDPE, [D-Pen 2,D-Pen 5]enkephalin an inactive ensemble of conformations (R) and an ensemble of active a The first four amino acids of each peptide type are in bold. The substitution X is conformations (R*). The inactive conformations, which do not activate given for each peptide within the family. intracellular partners, such as heterotrimer G proteins, are stabilized by b For nociceptin, the complete structure is provided, with the first four amino acids shown in bold. the presence of an Na+ ion, which forms a network with amino acids deep c The complete structures of the synthetic peptides are shown. Pen = penicillamine. in TM domains beneath the orthosteric site, and a “DRY” motif (Asp [or Glu]-Arg-Tyr) at the junction of TM3 and ICL2, which forms an “ionic were important for the analgesic effects. Although more recent studies lock,” and holds the receptor in an inactive conformation. Active recep- have not supported this concept (Gillis et al., 2020), the idea that selec- tor (R*) ensembles are formed in the presence of agonist and intracellular tive pharmacology could be gained in this way remains attractive. One binding partner through changes in several conserved “molecular switch” compound designated as a G protein-biased agonist, namely oliceridine, regions, including opening of the DRY-mediated ionic lock as well as col- has received approval for intravenous use in hospital settings in situations lapse of the Na+ binding site. These changes lead to an outward movement where other medications do not work, although the safety profile of olice- of TM6 relative to other TM domains. This opens a binding site for the ridine is no better than morphine. C-terminus of the Gα subunit of the heterotrimeric G protein, leading to activation of the G protein. The G protein and orthosteric binding sites are Allosteric Modulators. These are compounds that act at opioid allosterically linked. Thus, agonist binding increases G protein affinity and receptors but at a site distinct from the orthosteric site. Positive G protein binding increases agonist affinity. Most of this mechanism has allosteric modulators quantitatively alter the action of opioids occu- been determined through experiments with the β2 adrenergic receptor but pying the orthosteric binding site. As such, they can promote the applies equally well to opioid receptors (Weis and Kobilka, 2018). activity of endogenous opioid peptides to provide antinociception and so may have the potential to provide analgesia without the side Opioid Receptor Variants and Receptor Complexes effects associated with traditional opioid agonists. Negative allosteric There is growing evidence for increasing complexity of opioid receptor modulators inhibit the actions of opioid agonists but unlike naloxone function. For example, there are several nonsynonymous variants of the and naltrexone are not competitive. Thus far, positive and negative mu-opioid receptor found in the human population (Ravindranathan allosteric modulators are only in the early preclinical stages of inves- et al., 2009). Of these, the single polynucleotide polymorphism in the tigation (Livingston and Traynor, 2018). gene of the opioid receptor (OPRM1) A118G, giving a receptor in which https://ebooksmedicine.net/  448 β-LPH Pre-POMC JP ACTH γ-LPH Signal γ-MSH α-MSH CLIP β-MSH β-END Peptide Pre-Pro ENK Signal M M NK M M M L- M Peptide E -E -E -E -E -E -E N N N N N N K K K K- K K- CHAPTER 23 OPIOID ANALGESICS R R G F L Pre-Pro DYN Neo-END DYN A DYN B Signal L- L- L- Peptide E E E N N N K K K Figure 23–3 Opioid peptide precursors. Opioid peptides derive from precursor proteins that may also contain nonopioid peptides. Pre-POMC is a good example. Proteolytic processing of a pre-pro form by a signal peptidase removes the signal peptide; then, various prohormone convertases (endoproteases) attack at dibasic sequences, yielding α-, β-, and γ-melanocyte-stimulating hormone (MSH), ACTH, corticotropin-like intermediate lobe peptide (CLIP), β- and γ-lipotropin (LPH), and β-endorphin (β-END). In a similar manner, pre-pro enkephalin (ENK) yields Leu-enkephalin (L-ENK) and Met-enkephalin (M-ENK) and two extended derivatives, M-ENK-Arg-Gly-Leu and M-ENK-Arg-Phe. Pre-pro dynorphin (DYN) yields α neoendorphin (α-NEO) and dynorphin A and B (DYN A and DYN B), each of which contains the Leu-enkephalin sequence (Tyr-Gly-Gly-Phe-Leu) at its amino terminus. JP, joining peptide. Pre-pronociceptin (not shown) contains one copy of nociceptin peptide. For details of the proteolytic processing of POMC, see Figure 50–1. Agonists Delta-receptor Kappa-receptor Nociceptin-receptor O N N O O N N HN N N O O N SNC80 U69593 Ro64-6198 Antagonists N N N OH HO OH HO N O N N O H O N HN HO O OH HO Naltrindole Nor-BNI J113397 Figure 23–4 Examples of compounds acting at kappa, delta, and nociceptin receptor.  BOX 23–1 Pharmacology of Kappa-, Delta-, and NOP-Receptor Agonists 449 Kappa-opioid receptor agonists have analgesic effects (e.g., butorphanol, antidepressant-like, anxiolytic effects and anti-parkinsonian effects in pentazocine) but are not typically employed for long-term analgesic preclinical models (Dripps and Jutkiewicz, 2018). therapy because they can produce dysphoric and psychotomimetic NOPr agonists can be pro- or anti-analgesic depending on their site effects. Agonists acting at the kappa-opioid receptor inhibit the release of action and the animal species. NOPr agonists, unlike mu-opioid of oxytocin and antidiuretic hormone and cause prominent diuresis. receptor agonists, are not rewarding and do not cause respiratory Some kappa-opioid receptor agonists, such as salvinorin A from Salvia depression, so compounds with activity at both mu-opioid receptors divinorum, are used recreationally and have hallucinogenic effects in and NOPrs are being investigated as potentially safer analgesics. The humans. There is evidence that kappa-opioid receptor antagonists may system has been implicated in regulation of body weight and stress- have antidepressant effects in depressed patients (Jacobson et al., 2020). related mood disorders. Molecules targeting NOPr may find use in the Agonists at delta-opioid receptors have antinociceptive effects management of anxiety and/or depression and substance abuse (Witkin in animal models of neuropathic and chronic pain but have not yet et al., 2014). SECTION II found clinical utility because of preclinical and clinical evidence Some selective agonists and antagonists for these receptors are of proconvulsant activity. Delta-opioid receptor agonists also have shown in Figure 23–4. asparagine in position 40 of the N-terminus (Fig 23–1) is replaced by pharmacology. The exact nature of observed physiological responses aspartate, has received the most attention. This single nucleotide poly- induced by opioid agonists is due to the wide distribution of mu-opioid NEUROPHARMACOLOGY morphism is found in approximately 40% of Asian populations, 16% of receptors across the CNS and in the periphery, their degree of efficacy Europeans, and 3% of African Americans (Zerbino et al., 2018) and has (e.g., whether they are full or partial agonists), and the level of selectivity been linked to dependence on opioids and other drugs of abuse (Halikere of each drug for mu-opioid over other opioid receptors or, indeed, other et al., 2020). targets. Opioid drugs are relatively receptor selective at lower doses but Many splice variants of the mu-opioid receptor have been reported may interact with additional receptor types when given at high doses, and may show a differential pharmacology, although the roles and level especially as doses are escalated to overcome tolerance. Mu-opioid recep- of expression of these are not well known (Gretton and Droney, 2014). In tor agonists produce analgesia, affect mood and rewarding behavior, and addition, opioid receptors can form receptor complexes with themselves alter respiratory, cardiovascular, GI, and neuroendocrine function. The (homomers) or with other opioid receptors or indeed many other GPCRs, pharmacology of the non-mu-opioid receptor systems is briefly high- giving receptor complexes with the potential for a very diverse pharmacol- lighted in Box 23–1. ogy (Fujita et al., 2014). These aspects have potential clinical significance since drugs targeting splice variants or complex receptor heteromers could Pharmacology of the Prototypical Mu-Opioid have safer pharmacological profiles. Although the basis of much research, no clinical candidates targeting these entities have yet emerged. Agonist Morphine Analgesia Opioid drugs acting at the mu-opioid receptor, as exemplified by mor- Pharmacology of Clinically Employed phine, are used to treat different types of pain (Box 23–2). When thera- peutic doses of morphine are administered, patients report their pain to Opioid Drugs be less intense or entirely absent. Patients often report pain is still present, Clinically used opioid agonists are generally selective for mu-opioid but they feel less discomfort. In addition to relief of distress, some patients receptors and produce their therapeutic and adverse effects through may experience euphoria. Analgesia can be readily achieved without loss activation of these receptors. Even so, the drugs have a highly complex of consciousness, although drowsiness commonly occurs. Morphine at BOX 23–2 Pain States and Mechanisms Meaningful discussion of the action of analgesic agents must innocuous or mildly aversive stimuli (tepid bathwater on a sunburn; recognize that all pain is not the same and that a number of variables moderate extension of an injured joint). This pain typically reflects contribute to a patient’s pain reporting and therefore to the effect of the effects of active factors such as prostaglandins, bradykinin, the analgesic. Heuristically, one may think of pain as several distinct cytokines, serine proteases, and H+ ions, among many mediators. sets of events (Yaksh et al., 2015). Such mediators are released locally into the injury site and have the capacity, through eponymous receptors on the terminals of small, Acute Nociception high-threshold afferents (Aδ and C fibers), to activate these sensory Acute activation of small, high-threshold sensory afferents (Aδ afferents and to reduce the stimulus intensity required for their and C fibers) generates transient, stimulus-dependent inputs into activation (e.g., peripheral sensitization). In addition, the ongoing the spinal cord, which in turn leads to activation of dorsal horn afferent traffic initiated by the tissue injury and inflammation leads to neurons that project contralaterally to the thalamus and thence to the activation of spinal facilitatory cascades, yielding a greater output somatosensory cortex. A parallel spinofugal projection runs through to the brain for any given afferent input. This facilitation is thought the medial thalamus and thence to portions of the limbic cortex, such to underlie hyperalgesic states, for example, central sensitization. as the anterior cingulate. The output produced by acutely activating Such tissue injury/inflammation-evoked pain is often referred to as these ascending systems is sufficient to evoke pain reports. Examples nociceptive pain (Figure 23–5) (Sorkin and Wallace, 1999). Examples of such stimuli include a hot coffee cup, a needlestick, or an incision. of such states would be burn, postincision pain, abrasion of the skin, musculoskeletal injury, or inflammation of the joint. Tissue Injury Following tissue injury or local inflammation (e.g., local skin burn, Nerve Injury toothache, rheumatoid joint), an ongoing pain state arises that is Injury to a peripheral nerve yields complex anatomical and characterized by burning, throbbing, or aching and an abnormal pain biochemical changes in the nerve and spinal cord that induce response termed hyperalgesia, which can be evoked by otherwise spontaneous dysesthesias (shooting, burning pain) and allodynia https://ebooksmedicine.net/  450 (hurt from a light touch). Nerve injury pain state may not depend on Neuropathic pain is typically considered to respond less well to the activation of small afferents but may be initiated by low-threshold opioid analgesics than acute pain, and higher doses are required. sensory afferents (e.g., Aβ fibers). Such nerve injuries result in the There is a growing perception that, in the face of chronic tissue injury development of ectopic activity arising from neuromas formed by or inflammation (e.g., arthritis), there can be a transition from an nerve injury and the dorsal root ganglia of the injured axons as inflammatory to a neuropathic pain phenotype. well as changes in dorsal horn sensory processing. Such changes include activation of nonneuronal (glial) cells and loss of constitutive Sensory Versus Affective Dimensions of Pain Information generated by a high-intensity peripheral stimulus inhibitory circuits, such that low-threshold afferent input carried by initiates activity in pathways activating higher-order systems that Aβ fibers evokes a pain state (West et al., 2015). Examples of such reflect the aversive magnitude of the stimulus. Painful stimuli have the nerve injury–inducing events include mononeuropathies secondary certain ability to generate strong emotional components that reflect a to nerve trauma or compression (carpal tunnel syndrome) and distinction between pain as a specific sensation subserved by distinct the postherpetic state (shingles). Polyneuropathies such as those neurophysiological structures (the sensory discriminative dimension) CHAPTER 23 OPIOID ANALGESICS occurring in diabetes or after chemotherapy (as for cancer) can also and pain such as suffering (the original sensation plus the reactions lead to ongoing dysesthesias and evoked hyperpathias. These pain evoked by the sensation: the affective motivational dimension of the states are said to be neuropathic (Figure 23–6). Many clinical pain pain experience) (Melzack and Casey, 1968). Opioid drugs have syndromes, such as found in cancer, typically represent a combination potent effects on both components of the pain experience. of these inflammatory and neuropathic mechanisms. analgesic doses does not have anticonvulsant activity and usually does vomiting are common. Individuals may experience drowsiness, diffi- not cause slurred speech, emotional lability, or significant impairment of culty in mentation, apathy, and lessened physical activity. As the dose is motor coordination. Lower doses of morphine can produce reductions in increased, the subjective, analgesic, and toxic effects, including respira- the affective response to pain but not the perceived intensity of the pain tory depression, become more pronounced. experience; higher, clinically effective doses reduce both perceived inten- The analgesic actions of opioid drugs are mediated by actions in the sity and affective responses to the pain (Price et al., 1985). brain, spinal cord, and in some instances the periphery. These are sum- The relief of pain by morphine-like opioid agonists is relatively selec- marized in Figure 23–7. tive in that other senses are generally not affected, including light touch Supraspinal Actions. Direct microinjections of morphine into specific and proprioception. Continuous dull pain (as generated by tissue injury brain regions can produce potent analgesia that is reversible by the mu- and inflammation) is relieved more effectively than sharp intermittent opioid receptor antagonists, such a naloxone. The best characterized pain, such as that associated with the movement of an inflamed joint. of these sites is the mesencephalic PAG region. Morphine and other With sufficient amounts of opioid agonist, it is possible to relieve even the mu-opioid receptor agonists inhibit release of the inhibitory transmitter severe piercing pain associated with, for example, acute renal or biliary GABA from tonically active PAG systems that regulate activity in projec- colic, although opioids can induce spasm in the sphincter of Oddi and tions to the medulla. PAG projections to the medulla activate medullospi- may exacerbate the pain (see section on the GI tract, below). nal release of norepinephrine (NE) and serotonin (5HT) at the level of the When an analgesic dose of morphine is administered to normal, pain- spinal dorsal horn, which attenuate dorsal horn excitability (Yaksh, 1997). free individuals, the experience may be unpleasant, and nausea and Spinal Action. Opioid drugs delivered spinally (intrathecally or epi- durally) induce powerful analgesia that is reversed by low doses of sys- Injury temic naloxone (Yaksh, 1997). Mu-opioid receptors are largely limited to the substantia gelatinosa of the superficial dorsal horn, the region in Tissue injury which small, high-threshold sensory afferents terminate. A significant PG, BK, K proportion of mu-opioid receptors are associated with small peptidergic primary afferent C fibers; the remainder are on local dorsal horn neurons. Local release of active Sensitization Mu-opioid receptor agonists act presynaptically on small, high-threshold factors (PG, BK, K) primary afferents to inhibit the opening of voltage-sensitive Ca2+ channels, Persistent activation/ Neuroma sensitization of Aδ/C Spinal sensitization Nerve Injury Activity in ascending pathways + spinal facilitation Peripheral nerve Facilitation degeneration...Neuroma Exaggerated output for given stimulus input Spontaneous Spinal Aβ afferent afferent activity sensitization fibers Ongoing pain + Hyperalgesia Spontaneous dysesthesias Allodynia (shooting, burning pain) (light touch hurts) Figure 23–5 Mechanisms of tissue injury–evoked nociception. BK, bradykinin; K, potassium; PG, prostaglandins. Figure 23–6 Mechanisms of nerve injury–evoked nociception.  reflected by unexplained increases in pain reports, increased levels of 451 PAG OPIATE ACTION 2 pain with increasing drug dosages, or a diffuse sensitivity unassociated with the original pain (Lee et al., 2011). The mechanisms of this increased Periaqueductal pain profile are not understood, although evidence suggests that inflam- PAG gray matory responses may be involved through Toll-like receptor 4 activation GABA-ergic Dorsal neuron raphe on microglia, upregulation of proinflammatory cytokines, chemok- (tonically active) Locus ines, cyclooxygenase, and prostaglandin E2, and other neuropeptides, MOR activation 1 coeruleus such as cholecystokinin, neuropeptide FF, and nociceptin (Mercadante (inhibits GABA release) et al., 2019). Medullopetal neuron (GABA-R) Medulla 4 Respiratory Effects Although effects of mu-opioid receptor agonists on respiration are read- Medulla ily demonstrated in preclinical models, significant respiratory depression SECTION II SPINAL OPIATE 3 rarely occurs in the clinic with standard analgesic doses, unless there are ACTION mitigating factors where opioid drugs should be used with caution, for C-fiber terminal example, in patients with asthma, chronic obstructive pulmonary dis- ease (COPD), pulmonary hypertension, decreased respiratory reserve, MOR preexisting respiratory depression, hypoxia, or hypercapnia. Moreover, MOR Ca2+ it should be stressed that respiratory depression is the primary cause of deaths in opioid overdose in individuals who misuse and abuse opioids. NEUROPHARMACOLOGY K+ Mu-opioid receptor agonists depress all phases of respiratory activ- ity, including rate, minute volume, and tidal exchange, and produce Spinal cord irregular and aperiodic breathing. The diminished respiratory volume is due primarily to a slower rate of breathing, which after ingestion of 2nd-order neuron toxic amounts of opioids, may fall to three to four breaths per minute. Figure 23–7 Mechanisms of opioid action in producing analgesia. Top left: Morphine-like opioid agonists depress respiration through several mech- Schematic of organization of opiate action in the periaqueductal gray area anisms involving mu-opioid receptors. Respiratory rate and tidal vol- (PAG). Top right: Opioid-sensitive pathways in the PAG. Opioid actions via ume depend on intrinsic rhythm generators located in the ventrolateral the mu-opioid receptor block the release of GABA from tonically active sys- medulla. These systems generate a “respiratory rhythm” that is driven by tems that otherwise regulate the projections to the medulla (1), leading to an afferent input reflecting the partial pressure of arterial O2 as measured activation of PAG outflow that results in activation of forebrain (2) and spi- by chemosensors in the carotid and aortic bodies and CO2 as measured nal (3) monoamine receptors that regulate spinal cord projections (4), which by chemosensors in the brainstem. Morphine-like opioid agonists reduce provide sensory input to higher centers and mood. Bottom left: Schematic of respiration in part by a direct depressant effect on rhythm generation, primary afferent synapse with second-order dorsal horn spinal neuron, show- with changes in respiratory pattern and rate observed at lower doses ing pre- and postsynaptic opiate receptors coupled to Ca2+ and K+ channels, than changes in tidal volume. A key factor is the depression of the ven- respectively. Opioid receptor binding is highly expressed in the superficial tilatory response to increased CO2. This effect is mediated by depression spinal dorsal horn (substantia gelatinosa). These receptors are located presyn- of the excitability of brainstem chemosensory neurons. Also, opioids will aptically on the terminals of small primary afferents (C fibers) and postsyn- depress ventilation otherwise driven by hypoxia through an effect on aptically on second-order neurons. Presynaptically, activation of mu-opioid carotid and aortic body chemosensors. Importantly, hypoxic stimulation receptors blocks the opening of the voltage-sensitive Ca2+ channel, which oth- of chemoreceptors may still be effective when opioids have decreased erwise initiates transmitter release. Postsynaptically, mu-receptor activation the responsiveness to CO2, and inhalation of O2 may remove the resid- enhances opening of K+ channels, leading to hyperpolarization. Thus, an opi- oid agonist acting at these sites jointly serves to attenuate the afferent-evoked ual drive resulting from the elevated PO2 and produce apnea (Pattinson, excitation of the second-order neuron. 2008). In addition to the effect on respiratory rhythm and chemosensi- tivity, mu-opioid receptor agonists can have mechanical effects on air- way function by increasing chest wall rigidity and diminishing upper thereby preventing transmitter release. A postsynaptic action is demon- airway patency (Lalley, 2008). strated by the ability of opioid analgesics to block excitation of dorsal Studies comparing morphine and morphine-like opioids with respect horn neurons evoked by glutamate, partly by hyperpolarizing the neurons to the ratio of analgesic versus respiratory-depressant activity have found through the activation of K+ channels, making them less likely to fire. Mor- that when equianalgesic doses are used, there is no significant difference. phine selectively depresses the discharge of spinal dorsal horn neurons Maximal respiratory depression occurs within 5 to 10 min of intravenous evoked by small (high-threshold) but not large (low-threshold) afferent administration of morphine or within 30 to 90 min of intramuscular or nerve fibers. Overall, the capacity of spinal opioids to reduce the release subcutaneous administration. Maximal respiratory-depressant effects of excitatory neurotransmitters from C fibers and to decrease the excit- occur more rapidly with more lipid-soluble agents. After therapeutic ability of dorsal horn neurons accounts for the powerful and selective doses, respiratory minute volume may be reduced for as long as 4 to 5 h. effect of the drugs on spinal nociceptive processing. Agents that have persistent kinetics, such as methadone, must be carefully Peripheral Action. Direct application of high concentrations of opioid monitored, particularly after dose incrementation. Respiratory depres- analgesics to a peripheral nerve can produce a local anesthetic-like action sion produced by any mu-opioid receptor agonist can be reversed with an that is not reversed by naloxone. Conversely, at peripheral sites under opioid antagonist. It is important to remember that most opioid antago- conditions of inflammation where there is an increased terminal sensi- nists have a relatively short duration of action as compared with agonists tivity leading to an exaggerated pain response (e.g., hyperalgesia), direct such as morphine or methadone, and fatal “re-narcotization” can occur if injection of opioids produces a local action that can exert a normalizing vigilance is not exercised and if more antagonist is not added as needed. effect on the exaggerated thresholds. The effects may be on peripheral Factors Exacerbating Opioid-Induced Respiratory Depression. Sev- afferent terminals or on inflammatory cells that release products that sen- eral factors can increase the risk of opioid-related respiratory depression sitize the nerve terminal, or both (Stein and Machelska, 2011). even at therapeutic doses. These include the following: Opioid-Induced Hyperalgesia Other Medications. The combination of opioid drugs with other depres- A paradoxical increase in pain state can be observed following acute sant medications, such as general anesthetics, tranquilizers, alcohol, or (hours to days) or chronic opioid drug exposure. This increase may be sedative-hypnotics, produces additive depression of respiratory activity. https://ebooksmedicine.net/  452 Sleep. Natural sleep produces a decrease in the sensitivity of the medul- ADH and Oxytocin. The effects of opioids on ADH and oxytocin release lary center to CO2, and the depressant effects of morphine and sleep are are complex. These hormones are synthesized in the perikarya of the at least additive. Obstructive sleep apnea is a risk factor for increasing the magnocellular neurons in the paraventricular and supraoptic nuclei likelihood of fatal respiratory depression. of the hypothalamus and released from the posterior pituitary (see Age. Newborns can show significant respiratory depression and desat- Chapter 46). Morphine and morphine-like drugs bring about the lib- uration; this may be evident in lower Apgar scores if opioids are admin- eration of ADH by acting on the hypothalamic-hypophysial system. In istered parenterally to women within 2 to 4 h of delivery because of addition, mu-opioid receptor agonists may yield a hypotension second- transplacental passage of opioids. Elderly patients are at greater risk of ary to histamine release, which would promote ADH release. Endoge-