Section 2: Scientific Principles
Part B: Intravenous Anesthetics
Chapter 10: Intravenous Opioid Anesthetics

Site and Mechanism of Opioid Action

Opioid Receptors

In 1973, three independent teams of investigators described the presence of an “opioid receptor” in nervous tissue and hypothesized that endogenous substances probably stimulate this structure. 35, 36, 37  This rationale was supported by numerous observations, including the finding that naloxone could reverse footshock-induced analgesia. A few years later, the endogenous opiates were discovered (see later).

The original classification of opioid receptors was based on response patterns to three different opioid compounds in the chronic spinal dog model 38  and resulted in the description of three receptor types, named after the drugs used in the studies: m (morphine), k (ketocyclazocine), and s (SKF 10,047 or N-allylnormetazocine). The “s” receptor is no longer considered an opioid receptor but rather a highaffinity binding site for phencyclidine and related compounds. 39  In addition, s-receptor–mediated effects are enantio-selective for dextrorotatory, instead of levorotatory, compounds. Finally, s-receptor–mediated effects are not naloxone-reversible. In 1977, Lord and colleagues described a binding site in the isolated mouse vas deferens with high affinity for enkephalins. This opioid receptor site was named the d receptor, after deferens.

The profile of effects thought to be associated with a specific receptor is derived in numerous ways, including the potency and physiologic effects of a variety of agonist and agonist-antagonist interactions, the results of various bioassay and binding studies, structure-activity relationship data, and numerous other screening evaluations. For example, potency often correlates with receptor affinity and is described by the IC50 value, defined as the concentration of an agent that lowers the specific binding of3 H-naloxone by 50 percent. The greater the affinity of such an agent for a receptor, the lower the IC50, 31  and the smaller the dose and number of molecules necessary to occupy enough receptors to elicit a certain level of effect. Intrinsic efficacy, a property of drug-receptor interaction, is directly related to the number of spare receptors: the greater the intrinsic efficacy of a drug, the greater the receptor reserve.

Bioassay systems are used to help evaluate potency. The response to transmural electrical stimulation of a number of isolated tissues can be inhibited by opioids. This effect is most likely mediated by the presynaptic inhibition of transmitter release (neuromodulation). The two most important of these systems are the guinea pig ileum and mouse vas deferens. For example, morphine inhibits electrically induced contractions of the isolated guinea pig ileum. Data from these systems correlate well with opioid analgesic potency, 40  as determined by numerous intact animal and clinical evaluations. Biochemical characterizations of opiate receptors also have been used in receptor research. 31  Attempts to purify opioid receptors have been thwarted by their paucity in most tissues and chemical instability during isolation. Some investigators have reported the cloning and sequencing of opioid receptor types. 24  Five cDNAs that belong to the opioid receptor gene family have been cloned, but only three opioid receptor types (m, d, k), each arising from their own gene, have been pharmacologically defined. Three subtypes of each receptor have been proposed but have not yet been cloned (Table 10–3).

TABLE 10–3. Characteristics of Opioid Receptors

The m-opioid receptor manifests a high affinity for endogenous enkephalin, and the distribution of m-receptors and enkephalin mRNA is highly correlated. Investigations utilizing opiate receptor knockout mice demonstrate that morphine-induced analgesia is m-receptor–mediated. 41  Enkephalins also interact with d-receptors. k-Receptors, on the other hand, have high affinity for the endogenous opiate dynorphin.

m-Receptors are located in both the brain and spinal cord, with highest concentrations in the periaqueductal gray and substantia gelatinosa, respectively. m-Receptor opioidinduced analgesia is dose-dependent. Pharmacologic distinction of an analgesic m-receptor (m1 ) and a respiratory depression m-receptor (m2 ) is suggested, but it remains in question. 42, 43  A m3 -receptor may be involved in immune processes because it has significant distribution in astrocytes, endothelial cells, and macrophages. It is not clear whether or not these various receptor subtypes originate from separate genes or from post-translational modifications.

There is no selective systemic agonist available for d- receptors, and the enkephalins are rapidly degraded. The degree of analgesia that is produced by stimulation of the d-receptor is unclear (and may be more important at the spinal cord level). m1 -Receptors also appear more prominent in supraspinal analgesia, whereas d-receptors may be more important for spinal analgesia. 44  k-Receptors appear to play a role in producing mild to moderate analgesia at the spinal cord level for nonthermal painful stimuli (Table 10–4). The k-receptor agonist ethylketocyclazocine produces sedation and analgesia without causing much respiratory depression. 45  k-Receptor activation may explain in part some of the effects (analgesia with limited respiratory depression) of some mixed agonist-antagonists such as enalbuphine. 38  At least three separate k-receptor subtypes have been isolated. k3 -receptors are of particular interest because of their high density within the brain and association with supraspinal analgesia, whereas other k-receptors relate to spinal analgesia. 46 

TABLE 10–4. Supraspinal and Spinal Sites and Opioid Receptor Types Mediating Analgesia

Cellular Mechanisms

Opioid receptors belong to the superfamily of G protein– coupled receptors, all of which possess seven membrane-spanning regions. 24, 47  This group constitutes 80 percent of all known receptors and includes muscarinic, adrenergic, g-aminobutyric acid (GABA), and somatostatin receptors. The three opioid receptors have high amino acid sequence similarity to somatostatin receptors and very low similarity with all other receptors. The amino acid sequences of the opioid receptors are approximately 60 percent identical to one another, with greatest similarities existing in transmembrane and intracellular regions (Fig. 10–4). Specific amino acid sequences of the extracellular loops of opioid receptors are key in determining ligand-specific actions. Phosphorylation and glycosylation sites are responsible for a host of opioid-related effects including agonist-induced analgesia and desensitization or uncoupling of the receptor from G proteins. 48  Extracellular signal-related kinase activation may also contribute to opioid-induced biologic effects. 49 

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FIGURE 10–4 Proposed model for membrane topography of the rat m-opioid receptor. Amino acid residues of m-opioid receptor conserved in both d- and k-receptors, in either d- and k-receptors, and in neither d- nor k-receptor are shown by black, gray, and white circles, respectively. Branched structures show the potential N-linked glycosylation sites. (Reprinted from Minami and Satoh,51  with permission of Elsevier Science.)

Studies indicate both presynaptic (indirect) and post-synaptic (direct) facilitatory and inhibitory actions of opioids on synaptic transmission in many regions of the nervous system. Direct inhibitory actions of opioids are mediated by opioid receptors coupled to pertussis toxin–sensitive Gi /Go proteins and direct excitatory effects via a cholera toxin–sensitive Gs -like protein. The opioid receptor–activated G protein effector systems can be divided into two categories: short-term effectors (K+ and Ca2 + channels) and longer-term effectors involving second messengers such as adenylate cyclase/cyclic adenosine monophosphate (cAMP) and phosphatidylinositol. Both m- and d-receptors activate inwardly rectifying K+ channels and all opioid receptor types can inhibit the opening of voltage-dependent Ca2 + channels. m-Opioid agonists can also directly increase Ca2 + entry and cellular Ca2 + concentrations. 50  Changes in cAMP may underlie opioid-induced modulation of the release of neurotransmitters such as substance P. These previously mentioned actions account for many of the effects of opioids. For example, K+ channel effects result in hyperpolarization of neuronal membranes and decreased synaptic transmission. Decreases in Ca2 + influx can decrease neurotransmitter mobilization and release. Opioid-induced changes in Ca2 + concentration are likely to be a component of the mechanisms of opioid analgesia.

Opioids also have excitatory actions, indirectly by interneuron disinhibition and directly by neuronal excitation, via Gs proteins. This may explain some neuroexcitatory responses to opioids.

Mechanisms of Analgesia

There is significant concordance between specific receptor mRNA expression in the central nervous system (CNS) and binding of specific receptor ligands 51, 52  (see Table 10–4). Many of these areas are in major ascending and descending pain pathways (Fig. 10–5). The transport of opioid receptors is thought frequently to underlie differences that exist in receptor mRNA and ligand binding distributions. Research on opioid receptors has entered a new era in which receptors can be examined with dual labeling techniques utilizing both specific ligands and gene structure and mRNA expression. Resultant anatomic studies will help to characterize the phenotype and function of CNS centers, nuclei, and even individual cells. 52 

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FIGURE 10–5 Diagram illustrating proposed antinociceptive mechanisms of morphine in the central nervous system.

Numerous studies do demonstrate opioid action and behaviorally defined analgesia in many CNS sites. These include the amygdala, the mesencephalic reticular formation, the periaqueductal gray matter, and the rostral ventral medulla. However, the role of some of the higher brain structures containing opioid receptors in opioid analgesia remains obscure and controversial. The proposed mechanisms by which opioids alter nociception are summarized in Figure 10–5.

The periaqueductal gray area is one of the regions in the brain stem where microinjections of morphine or direct electrical stimulation produce analgesia that can be blocked with naloxone. 53, 54, 55  Stimulation of periaqueductal gray receptors with morphine, electricity, or endogenous opiate-like peptides results in impulses that alter the degrees of inhibition of different neuronal pools and contribute to reducing the transmission of nociceptive information from peripheral nerves into the spinal cord and up the neuraxis. 55  Opioid actions at the periaqueductal gray area influence, through direct neural connections, the rostral ventromedial region of the medulla. This region of the medulla, in turn, modulates nociceptive transmission neurons in the dorsal horn of the spinal cord. The integrity of such neurotransmitter systems connecting the pain-inhibiting system in the brain to the spinal cord is necessary for morphine to exert its full analgesic action. Thus, opioids do not only produce analgesia by direct actions. Whereas opioid application at the spinal cord, for example, produces analgesia at the level of administration, neurally mediated actions at distant CNS sites also enhance analgesia. The systemic administration of opioids activates the analgesic “system” in the CNS. 56 

Local spinal mechanisms, in addition to descending inhibition, underlie the analgesic action of opioids. Opioids act at nerve synapses either presynaptically (as neuromodulators) or postsynaptically (as neurotransmitters) (Fig. 10–6). 57  The substantia gelatinosa of the spinal cord possesses a dense collection of opiate receptors. 29, 58  Direct application of opioids to these receptors creates intense analgesia. Spinal cord presynaptic substance P release in primary sensory neurons is inhibited by m-, k-, and d- agonists and is one neuraxial mechanism of opioid analgesia. 59 

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FIGURE 10–6 A schematic diagram illustrating the release of the excitatory transmitters from C fibers and the subsequent effects on a dorsal horn nociceptive neuron. The predominant presynaptic action of opioids (reducing the release of these transmitters) and the postsynaptic action (reducing neuronal activity) are shown. (From Dickenson57 )

Opiate receptors are also localized in the substantia gelatinosa of the caudal spinal trigeminal nucleus, the nucleus receiving pain fibers from the face and hands via branches of the fifth, seventh, ninth, and tenth cranial nerves. 53  Opioids inhibit neuronal excitation of the dorsal horn in response to painful sharp stimulation, and sensations via A delta fibers are reduced. Excitatory postsynaptic potential summation is also blocked by opioids in the dorsal horn blocking the development of dull persistent pain transmitted via C fibers. This summation is much easier to block than to treat and underlies the concept of preemptive analgesia as well as the clinical observation that patient responses to surgery are easier to control with opioids before rather than after stimulation. Opioids also affect second-order neurons by preventing excitatory threshold reductions and receptive field expansions at the spinal cord level. Opioids may also inhibit the early expression of DNA that is integral to transforming cellular characteristics necessary for the development of chronic or persistent pain (see Fig. 10–6).

Opioids may also produce some analgesia via peripheral mechanisms outside the CNS 60  (Fig. 10–7). Not all studies confirm this capacity in humans, 61  and the clinical relevance of this phenomenon appears to be negligible. 62  Factors affecting the efficacy of opioid action in the periphery, such as inflammation, may be important. Opioid receptors located on primary afferent neurons are likely sites of action, and immune cells infiltrating inflamed tissue may produce the endogenous ligands for these peripheral receptors.

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FIGURE 10–7 Schematic representation of possible peripheral opioidergic mechanisms. The neuronal cell body is located in the dorsal root ganglion. Opioid receptors are transported toward its central (right) and peripheral (left) terminals. After stimulation with cytokine (interleukin-1) or corticotropinreleasing hormone, opioid peptides are released from monocytes or macrophages (M) or lymphocytes (L). Occupation of neuronal opioid receptors by these ligands decreases the release of excitatory (proinflammatory) neuropeptides (e.g., substance P or calcitonin-gene–related peptide) and the excitability of the primary afferent neuron. (From Stein60 )

Several other mechanisms of opioid action have been suggested. Opioid agonists produce a local anesthetic-like effect on the surface of excitable cell membranes that does not involve a stereospecific receptor and may contribute to some of their actions. 63  More recent work suggests that the local anesthetic effects of opioids, most prominent with meperidine, occur at the proximal end of the dorsal root as it passes the dorsal root entry zone. 64  Serotoninergic pathways may also in part modulate opioid-mediated analgesia. 65  Some opioid effects may be elicited at GABA receptors. Finally, it has also been postulated that opioid anesthesia may involve a general membrane effect because of much closer correlations between electroencephalographic (EEG) or anesthetic effects and membrane lipid content as opposed to serum opioid levels. 66 

Tolerance is a diminished response to opioid action and occurs within hours to days or weeks. Tolerance may represent an uncoupling of the usual drug-receptor effect. It may result from downregulation of the number of receptors and/or their affinity for agonists or an uncoupling between the receptor and intracellular second messengers via increases in adenyl cyclase activity. Tolerance may also develop as a result of other compensatory cellular responses to the presence of continuous opioid action that result in the restoration of cAMP homeostasis. 67  The level of expression of m-opioid receptor mRNA is not static, and its regulation by protein kinase C activation, with subsequent phosphorylation of opioid receptor protein, contributes to alterations in responsiveness to opioid agents in long-term opioid use. 68  Interestingly, there is little cross-tolerance between most receptor subtypes. In addition, the most potent opioid agonists with the largest receptor reserve, such as sufentanil, appear to be least prone to producing tolerance. 69  Tolerance is surmountable by increasing dose, at least initially.

Receptorology has also helped delineate, through receptor pharmacokinetic studies, how certain drugs can have a duration of action that extends well beyond what the plasma half-life would predict. For example, buprenorphine‘s dissociation from the m-receptor is much slower than fentanyl‘s and does not parallel plasma concentrations. 70  The high affinity of buprenorphine for m-receptors also accounts for the difficulty of reversing its effects with naloxone.

Other pharmacologic phenomena have been explained by radioligand-receptor studies. The concentration and proportion of the receptor subtypes can change with time. For example, m1 -receptors increase in number and concentration as newborn mice grow and thus provide more analgesia after a similar dose of an opioid agonist. 71  A marked and widespread disappearance of m- and d-receptors has been shown to occur in the aging brain. 72  Interestingly, the opposite occurs with benzodiazepine receptors during aging, a finding indicating that these effects are specific and are not representative of a general phenomenon.

The presence of opioid receptors in other areas of the CNS (e.g., basal ganglia, limbic area, cerebral cortex) suggests other roles for the endogenous opiates and their receptors. The cardiovascular system possesses opioid receptors that have been documented by radioligand studies to exist in the heart, the cardiac branches of the vagus and sympathetic nerves, the central cardiovascular regulatory centers, and the adrenal medulla. 73  Receptor-mediated opioid effects, as discussed later, indicate potential roles for and implications of opioids in shock, myocardial ischemia, ischemic preconditioning, and other cardiovascular events.