P cr k

Figure II-9. Difference in topographic density of the three opioid receptor sites within the central nervous system. Adapted from [3]

normally serve endogenous opiates (the endorphins, dynorphins, and enkephalins;

1. Activation of the mu receptors results in analgesia, euphoria, respiratory depression, nausea, GI slowdown, and miosis. Receptors of this type are mostly located in periaquaductal gray (PAG), spinal trigeminal nucleus, caudate and geniculate nuclei, thalamus, and spinal cord.

2. Binding at the kappa receptors (k) induces modest analgesia, dysphoria, feelings of depersonalization and disorientation, miosis, and mild respiratory depression. These receptors are mainly found in basal ganglia, nucleus accumbens, ventral tegmentum, cortex, hypothalamus, periaqueductal grey, the spinal cord, and in the periphery.

3. Occupation of the delta receptors (8) results in anxiolysis and central pain relief, although its overall significance is not all that well understood. They are mainly found in the nucleus accumbens and the limbic system (Table II-2).

Molecular biology techniques have enabled the primary amino acid sequence of the human k-, and 8-opioid receptors to be determined. The pharmacological and functional properties of the cloned receptors, the development of "knockout" animals, which are deficient in a receptor or part of a receptor, and the manipulation and substitution of various amino acids in critical domains of the various opioid receptors have provided new insights in opioid action. In this regard, the three opioid receptor genes, encoding mu (MOR), delta (DOR), and kappa (KOR) have been cloned. The binding affinities of a range of opioids to the k-, and 8-opioid receptors and also to the cloned orphinan receptor have been examined in animals. The animal data indicate that while the commonly prescribed opioids (agonists and antagonists) bind preferentially to the ^-receptor, they also interact with all three receptor types. Morphine and normorphine (a minor metabolite of morphine) show the greatest relative preference for the ^-receptor. Methadone (which also has some NMDA-receptor blocking activity) shows significant binding to -receptors, while buprenorphine, and to a lesser extent naloxone, avidly binds to all three receptor types. There is evidence (albeit inconsistent) that the D-enantiomer of methadone blocks the NMDA receptor [6]. The binding affinity of buprenorphine to the ^ receptor is much greater than that of naloxone, which explains why the latter only partially reverses buprenorphine overdose.

Animal data also indicate that codeine and diamorphine have very poor binding to opioid receptors, which reinforces the possibility that both are prodrugs where the pharmacologically active species are morphine [7] and 6-monoacetyl morphine, respectively [8]. Oxycodone may also act through an active metabolite, though there are some data, which suggest that this is not the case [9]. Pethidine is considered to be a potent ^-receptor agonist, but it does bind weakly to all three opioid receptors (Table II-1). Ketobemidone has a lower affinity for the ^-receptor than does morphine, but it shows greater discrimination for this receptor compared to K-receptors. The binding of both of these opioids to the 8-receptor is similar [10].

This difference in opioid action is also mirrored in the difference in affinity of various narcotic ligands interacting with the three relevant opioid receptor sites (Table II-3). It should be noted that some of those ligands, either pure antagonists, mixed agonist/antagonists or partial agonists, are characterized by displacement potency at a specific receptor site.

From the above binding and displacement values it can be seen, that opioid practically bind to all three receptor sites, however with different affinity. The preference in binding to one receptor site manifests itself in the visible clinical effect, which may either be of agonistic or of antagonistic nature.

The binding of morphine, methadone, buprenorphine, and naloxone to the cloned human ^-receptor shows excellent congruence with the animal data [16]. Fentanyl shows a similar binding affinity, while codeine demonstrates greater binding affinity to the cloned human receptor (Table II-3; Figure II-10). Thus, for these commonly administered opioids, there is no great variability in their affinity for the human receptor. The clinical relevance of these data is that different opioids act in different ways. From anecdotal clinical experience there is considerable interindividual

Table II-3. Binding affinity (nmol/l) of various opioids to the three main opioid receptor sites measured in guinea pig brain homogenates. The lower the value the better the fit of the ligand to the respective receptor site and the better their efficacy. Ligands with "*" demonstrate antagonistic potency at the specific receptor site

Table II-3. Binding affinity (nmol/l) of various opioids to the three main opioid receptor sites measured in guinea pig brain homogenates. The lower the value the better the fit of the ligand to the respective receptor site and the better their efficacy. Ligands with "*" demonstrate antagonistic potency at the specific receptor site

Opioid ligands

Delta (8)

Kappa (k)

Mu ()

Morphine

90

317

1.8

Normorphine

310

149

4.0

Levorphanol

5.6

9.6

0.6

Codeine

>1000

no data

2700

Methadone

15.1

1628

4.2

Fentanyl

151

470

7.0

Alfentanil

21.200

>10.000

30

Sufentanil

23

124

1.6

Lofentanil

0.24

0.6

0.023

Carfentanil

3.3

43

0.024

Pethidine

4345

5140

385

Pentazocine

106

22.2

7.0*

Butorphanol

13

7.4

1.7*

Nalbuphine

163

66

6.3*

(±)Pentazocine

467

8.7

39*

Buprenorphine

1.3*

2.0*

0.6

Naloxone

27'

17.2*

1.8*

Naltrexone

9.4*

6.5*

0.46*

Cyprodime

356'

176*

0.4*

(—)Bremazocine

0.78

0.075

0.62*

(±)Tifluadom

290

4.1

22*

(±)U50,488H

9200

0.69

435*

(—)Ethylketazocine

5.2

2.2

2.3

Leu-Enkephalin

1.8

>10.000

150

variability in response to each opioid and this reinforces the need to assess an individual's response to opioid analgesia carefully. It also is premature to extrapolate from laboratory data, which in many instances have not yet been replicated, to the clinic. However, data increasingly inform the clinical use of these drugs and will be particularly relevant to new approaches to their use such as "opioid switching".

Figure II-10 shows the putative analgesic effect mediated by the main ^-opioid receptor depicting that higher affinity also correlates closely with analgesic potency. But aside from ^-receptor interaction, analgesia can also be mediated through a K-receptor and a 8-receptor site. The classification of different opioid receptor types is based on the original description by Martin and coworkers from 1976 [5]. The effects presumed to be mediated at ^-receptors have been defined as a result of both human and animal studies, while the effects mediated at k-receptors derive predominantly from animal models. Receptors mediate analgesia that persists in animals made tolerant to ^-agonists. The K-agonists produce less respiratory depression and miosis than ^-agonists. It is assumed that k opioid receptors mediate

Boy Growth Chart Gestation
Figure II-10. Difference in affinity of various opioids at the ^-receptor site. Ligands with an asterix reflect antagonistic activity at this site

the sedative and mental clouding effects of opioids, in addition to their other pharmacological actions.

Opioid receptors are found in several areas of the brain, particularly in the periaqueductal grey matter, and throughout the spinal cord (Figure II-9). Supraspinal systems have been described for k-, and S-receptors, whereas and K-receptors modulate pain at the spinal level [3, 17, 18].

The different distribution of the various opioid subsites suggests different mechanisms of action in the mediation of analgesia. Thus, ^-selective opioids like morphine, fentanyl and sufentanil, due to the high density of binding sites, mediate their main action within the brain stem and the midbrain. Due to their close vicinity to respiratory and cardiovascular regulating centers in the brain stem, selective ^-opioids accordingly induce a marked depression of respiration and blood pressure. On the other hand, due to the main distribution of the K-receptors within the cortex (lamina V, VI) [19] it is conceivable that these ligands induce a lesser respiratory and cardiovascular depressive effect. As a consequence and contrary to ^-ligands, K-ligands induce a marked sedative appearance. In addition, there is a lesser addiction liability with K-ligands, which is easily derived from the fact that the relevant areas in the limbic system show a low concentration of K-binding sites. Also, the lesser analgesic potency of K-ligands is enlightened by the fact that most of the K-selective receptors can be found in the deep lamina VI of the cortex. Since their dendrites retrograde descend to the thalamus, all ascending nociceptive input is modified, resulting in a depression of nociceptive afferences and a reduction in arousal. Certain dendrites of petrosal cells of the cortex also descend down to the brain stem, whereby the activating, ascending reticular system (ARS) is affected resulting in a reduction of vigilance [20].

In summary, due to the dissimilarity of distribution of the three opioid receptor subtypes with the spinal cord and the supraspinal areas of the CNS, a functional differentiation can be expected. This effect is reflected in difference of binding affinities with the brain where 22% of all receptor sites are referred to the 36% to the k- and 42% to the 8-opioid receptor [20, 21]. The present understanding of the effect profiles of opioid receptors, however, remains incomplete, as new advances make it clear that their disposition and structure are extremely complex. Opioids inhibit pain signals by different mode of actions:

• Inhibition of Ca++-influx into the buttons of the presynaptic cell (e.g. the one releasing Substance P; Figure II-11). This is because Ca++-influx is necessary for neurotransmitter release, whereby opioids reduce or prevent Substance P from being released.

• Acting as an inhibitory neurotransmitter, since the opioid hyperpolarizes the postsynaptic cell by enhancing K+-flow out of the neuron, which makes it more difficult for all incoming nociceptive afferences to stimulate the next neuron, and thus more difficult to send painful information.

• Moderation of central perception of painful information in the limbic system so as to make it less aversive when it is perceived.

Several facts have led to the assumption that opioids interact with specific binding sites in the CNS. A slight molecular substitution at the side chain of the morphine molecule structure results in considerable changes of potency (Table II-5).

Whereas pethidine (meperidine, USP), a piperidine derivative, may be considered a weak analgesic, fentanyl, a piperidine derivative, is about 100-300 times more potent than morphine. The opioid antagonists levallorphan and naloxone are noted for a low and a analgesic effect, respectively. Furthermore, only the levorotator (levo-) isomers of opioids, which appear in their natural form (i.e. compounds which, when in solution, rotate plane-polarised light to the left) are pharmacologically active (e.g. levorphanol). Their dextrorotatory (dextro-) isomers, which can be synthesized in the laboratory (e.g. dextrophane), shows a negligible pharmacological effect. Both substances are structurally the mirror image of each other (Figure II-12).

In this context it is important to note that only the levo-stereoisomer of the racemic mixture is the pharmacologically active ingredient. This observation supports the

Figure II-11. Mechanism of action of opioids at the central nervous system. By binding at the same receptor site as the endogenous opioids (i.e. enkephalins, endorphins), the release of excitatory neuro-transmitters such as acetylcholine and glutamate is decreased thereby reducing the receiving cells excitatory input. The degree of opiate receptor binding is proportionally to the net release of excitatory transmitters and the reduction of depolarization produced by the arriving nociceptive nerve impulse. This enkephalin inhibitory system normally modulates the activity of the ascending pain pathways within the spinal cord and the brain. Opioid agents act by binding to unoccupied enkephalin receptors, thereby potentiating the analgesic effects of the system notion that stereroselectivity of an opioid analgesic is a prerequisite in order to bind to the opiate receptor site, thus inducing analgesia.

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