Specific Binding Sites For Opioids In The

In addition, a substitution at the side chain, for example the substitution of a methyl-group by an allyl-group or the substitution by a cyclopropyl-group results in the new opioid antagonist naloxone, diprenorphine and naltrexone respectably, or mixed agonists/antagonists (nalorphine, levallorphane), which have the capability of antagonizing the effect of the parent compound (Figure II-14).

Similarly, when the N-methyl group of the highly potent opioid oxymorphone or the pure agonist etorphine (1000 times of morphine) is replaced by a cyclo-propylmethyl group, the highly potent antagonists naltrexone and diprenorphine are derived. These compounds are 2.5 times as potent as naloxone and while the former is used as an oral preparation in the rehabilitation of the earlier opiate addict, the latter is used in veterinary medicine for the reversal of immobilization of wild animals. In addition, diprenorphine is also the original substance of buprenor-phine where additional three methyl groups are incorporated in the molecule (Figure II-15).

Such minor changes in the molecular structure and their resultant major pharmacological effect suggest, that similar to hormones and catecholamines, opioids

Morphine Nalorphine
Figure II-14. Molecular structure of the mother compounds morphine, levorphanol and oxymorphone (15 times morphine), all pure agonists, where substitution of the N-methyl group by an allyl-group results in mixed agonists antagonists (nalorphine, levallorphane) or the pure antagonist naloxone

bind with specific receptor sites which results in the characteristic effects such as analgesia. Various research groups corroborated this hypothesis almost simultaneously. Pert and Snyder [17], Terenius [25] and Kosterlitz [26] were the first research group to identify selective binding sites in the CNS using radioactive labeled opioids. These so-called opiate binding sites were found mainly in neuronal structures and nervous pathways involved in the transmission of nociceptive signals such as the first relay station of pain transmission, the substantia gelatinosa of the spinal column. In the posterior horn the impulse is passed over to the second

HO Oft

Oxymorphone

HO Oft

Naltrexone

Oxymorphone

Etorptilne

Figure 11-15. Chemical structures of the pure agonists oxymorphone (Numorphane®) and etorphine (Immobilone®) and their derivatives naltrexone (Trexane®) and diprenorphine (Revivon®) respectively, both of which are pure opioid antagonists no gCH Diprenorptilne

Etorptilne

Figure 11-15. Chemical structures of the pure agonists oxymorphone (Numorphane®) and etorphine (Immobilone®) and their derivatives naltrexone (Trexane®) and diprenorphine (Revivon®) respectively, both of which are pure opioid antagonists neuron while, simultaneously, descending nerve fibers from the reticular system (the cortico- and reticulo-spinal tract) induce either a facilitation or an attenuation of pain transmission, which results in a modulation of pain impulses at the spinal level (Figure II-11). The course of pain transmission is to the contralateral side of the spinal cord where impulses have already undergone a distinct separation. It is the paleospinothalamic pathway, consisting of nonmyelinated C-fibers, which mediate the excruciating, dull pain component, which is difficult to localize as it ends in the nonspecific nuclei of the medial thalamus [27]. En route, the paleospinothalamic tract sends off afferent fibers to the midbrain area, such as the periaqueductal grey matter and the reticular formation [28]. The pathway ends in intralaminar nuclei of the thalamus and the nucleus limitans, a patch of pigmented nerve cells border the mesencephalon (Figure II-16).

From there, subcortical pain pathways link with the pallidum, the alleged psychomotoric center that sends fibers to all areas of the brain hemisphere. The neospinothalamic pathway, in contrast, consists of myelinated A82-fibres, which transfer impulses to the nucleus ventrocaudalis-parvocellularis (N.v-c parvocellu-laris). From there pain sensations are projected to the postcentral gyrus, which enables the patient to localize the source of pain (Figure II-16). Both, the central grey matter and the pallidum are characterized by a dense accumulation of opiate binding sites [29, 28]. It is worth noting that nervous pathways transmitting the dull, chronic and less pinpointed pain components are more affected by opioids, while

Figure II-16. The nucleus limitans, lying adjacent to the nucleus ventro-caudalis-parvocelluraris (N.v-c parvocellularis), is an important relay station in the mediation of nociceptive afferents to higher pain modulating and discriminating centers of the CNS, which is necessary for the nonspecific feeling of pain and is closely coupled with emotions

Figure II-16. The nucleus limitans, lying adjacent to the nucleus ventro-caudalis-parvocelluraris (N.v-c parvocellularis), is an important relay station in the mediation of nociceptive afferents to higher pain modulating and discriminating centers of the CNS, which is necessary for the nonspecific feeling of pain and is closely coupled with emotions the neospinothalamic pathway conveys the sharp and well localized pain components which accompany any injury and are always the first to be perceived. The indefinable, dull, emotional component is perceived later, giving pain its negative character. This separation in pain pathways is of special importance. Impulses from the fast pathway usually antagonize the mediation of slow afferent impulses on all levels in the CNS: substantia gelatinosa and reticular formation, as well as the specific and the nonspecific projecting nuclei of the thalamus [30]. Opioid binding sites, as they are visualized with receptor-binding techniques, strikingly map the paleospinothalamic pain pathway (Figure II-17). Furthermore, there is a high density of opioid binding sites in various other parts of the brain [3, 17, 18, 31]:

1. The corpus striatum, being part of the limbic and the extrapyramidal motor system, is responsible for triggering opioid-induced muscular rigidity. It is not only the regulatory center for locomotion but it is also the center for the regulation of attention and perception.

2. The area postrema in the brain stem where opioids apparently induce respiratory depression, nausea and vomiting.

3. The caudal portion of the trigeminal nucleus being responsible for the transmission of painful afferences from the face and head.

Hypothalamus

Cingutate Cor

Thalamus

Hypothalamus

Cingutate Cor

Thalamus

Cortex

Periaqueductal

Periaqueductal

Substantia Gelatinosa

Substantia Gelatinosa

Figure II-17. The different areas within the central nervous where a dense accumulation of opioid receptors can be found

4. The nucleus solitary tract in the brain stern, which is the origin of the noradren-ergic dorsal pathway bundle, which is in command of vigilance and the cough reflex.

5. The nuleus amygdala, being part of the limbic system, is in charge of the mediation of euphoria (or "kick") when opioids are used for other purposes than pain.

6. The locus coeruleus being the origin of the neurosympathetic system in the brain stem, regulates peripheral vasodilatation.

7. Lastly, a dense accumulation of opioid binding sites is found in the substantia gelatinosa at the dorsal horn of the spinal cord.

- Current thinking is that effective opioid analgesics work through stimulating mu receptors, which also produce euphoria.

- Euphoria is mediated by the actions of opiates at a cluster of brain areas that include the nucleus accumbens and ventral segmental area. Dopamine influx seems to cause subjective pleasure, or euphoria.

- Opioids may have a "disinhibiting" (inhibition of inhibitory neurons) effect that allows greater dopamine influx.

Because the main property of opioids is the blockade of nociceptive transmission in the mesencephalon (i.e. the nucleus limitans and the limbic system) the following effects can be observed:

1. No pain (analgesia), since any sensation is not identified as painful.

2. A lack of the negative emotional component of pain. On the contrary, euphoria may result and pain is no longer experienced as an emotional distress, even though pain impulses are transmitted via the ventrocaudal-parvocellular nucleus to the postcentral cortex.

3. During the opioid-induced pain-free state, the site of pain, however, still can be localized. As a consequence pain has lost its negative character and is no longer experienced or perceived as uncomfortable and distressing.

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