78
5
tissue damaging mechanical stimuli, thermal stimuli or factors released from damaged or
inflamed tissue and transmits it to the dorsal horn of the spinal cord. The second-order
neuron forms a synapse with the first one in the spinal cord and transmits information to
the thalamus. The third-order neuron then synapses with the second one and transmits
information to the somatosensory cortex (Cross 1994). The modulation of pain perception is achieved by descending nerve tracts from the brain (especially the periaqueductal
grey matter, PAG) transmitting signals to the spinal cord, mostly ending in spinal interneurons. These interneurons release endogenous opioids, which activate μ-opioid receptors in dorsal horn neurons and thereby inhibit pain transmission. Moreover, descending
nerve tracts in the PAG are blocked in the absence of pain signals by GABAergic inhibitory interneurons. In response to ascending pain signals, this block is released by enkephalin signalling. In addition, opiate receptors in dorsal horn neurons are also activated by
peripheral mechanical stimuli (like normal and therefore not painful touch) to prevent
pain transmission to the thalamus. This is the reason why rubbing injured body parts
immediately after the insult partially releases pain. In summary, signalling at opioid
receptors very specifically blocks the perception of pain.
Opioid signalling also occurs in certain areas of the brain and induces psychological
effects such as euphoria and feelings of pleasure and reward. This is caused by excessive
release of dopamine. In addition, opiate receptors are located in the respiratory centre of
the brainstem where they are involved in controlling the breathing rate. Overdoses of
heroin or morphine can arrest breathing altogether, causing death.
Opioid receptors transduce signals in a cell type-specific manner dependent on posttranslational modifications of the intracellular domains of the receptors. Originally it was
shown that they couple to pertussis toxin-sensitive G-proteins. These include G i1–3 and
G oA/B , both AC inhibitors. They can also be coupled to pertussis toxin-insensitive
G- proteins, including G q 14 and 16, activating PLC and neuronal G i (Gz) and G s , which
affect AC and the opening of cAMP-dependent Ca 2+ - and Na + -channels. Finally, the β/γsubunits of several G-proteins modulate the activities of a number of enzymes including
AC 2,4,7, PLC, MAPK and others (Tso and Wong 2003).
Opioids are two-faced. They belong to the most effective painkillers in the world yet
also induce the most severe tolerance and withdrawal symptoms. Responsible for the
adverse effects of opioid consumption are molecular and cellular adaptations to repeated
stimulation with opioids. In the centre of these adaptations is an enhancement of the AC
responsiveness – so-called AC superactivation. This effect is specific for pertussis toxinsensitive G i -signalling. The molecular mechanism is not clear yet. Involvement of G s signalling and Gβ/γ signalling and post-translational modifications of AC and other proteins
are discussed.
Interestingly, the selective κ-opioid receptor agonist Salvinorin A from the plant Salvia
divinorum is investigated as a drug with potential to treat addiction, e.g. for cocaine and
morphine (Kivell et al. 2014; Simonson et al. 2015). This is supposed to be due to the
interaction of κ-opioid receptors with the dopamine system. In particular, it has been
shown that κ-agonists increase the extracellular dopamine concentration by an as yet
unclear mechanism (. Table 5.1).
Chapter 5 · GPCRs as Targets for Plant-Derived Drugs
5
tissue damaging mechanical stimuli, thermal stimuli or factors released from damaged or
inflamed tissue and transmits it to the dorsal horn of the spinal cord. The second-order
neuron forms a synapse with the first one in the spinal cord and transmits information to
the thalamus. The third-order neuron then synapses with the second one and transmits
information to the somatosensory cortex (Cross 1994). The modulation of pain perception is achieved by descending nerve tracts from the brain (especially the periaqueductal
grey matter, PAG) transmitting signals to the spinal cord, mostly ending in spinal interneurons. These interneurons release endogenous opioids, which activate μ-opioid receptors in dorsal horn neurons and thereby inhibit pain transmission. Moreover, descending
nerve tracts in the PAG are blocked in the absence of pain signals by GABAergic inhibitory interneurons. In response to ascending pain signals, this block is released by enkephalin signalling. In addition, opiate receptors in dorsal horn neurons are also activated by
peripheral mechanical stimuli (like normal and therefore not painful touch) to prevent
pain transmission to the thalamus. This is the reason why rubbing injured body parts
immediately after the insult partially releases pain. In summary, signalling at opioid
receptors very specifically blocks the perception of pain.
Opioid signalling also occurs in certain areas of the brain and induces psychological
effects such as euphoria and feelings of pleasure and reward. This is caused by excessive
release of dopamine. In addition, opiate receptors are located in the respiratory centre of
the brainstem where they are involved in controlling the breathing rate. Overdoses of
heroin or morphine can arrest breathing altogether, causing death.
Opioid receptors transduce signals in a cell type-specific manner dependent on posttranslational modifications of the intracellular domains of the receptors. Originally it was
shown that they couple to pertussis toxin-sensitive G-proteins. These include G i1–3 and
G oA/B , both AC inhibitors. They can also be coupled to pertussis toxin-insensitive
G- proteins, including G q 14 and 16, activating PLC and neuronal G i (Gz) and G s , which
affect AC and the opening of cAMP-dependent Ca 2+ - and Na + -channels. Finally, the β/γsubunits of several G-proteins modulate the activities of a number of enzymes including
AC 2,4,7, PLC, MAPK and others (Tso and Wong 2003).
Opioids are two-faced. They belong to the most effective painkillers in the world yet
also induce the most severe tolerance and withdrawal symptoms. Responsible for the
adverse effects of opioid consumption are molecular and cellular adaptations to repeated
stimulation with opioids. In the centre of these adaptations is an enhancement of the AC
responsiveness – so-called AC superactivation. This effect is specific for pertussis toxinsensitive G i -signalling. The molecular mechanism is not clear yet. Involvement of G s signalling and Gβ/γ signalling and post-translational modifications of AC and other proteins
are discussed.
Interestingly, the selective κ-opioid receptor agonist Salvinorin A from the plant Salvia
divinorum is investigated as a drug with potential to treat addiction, e.g. for cocaine and
morphine (Kivell et al. 2014; Simonson et al. 2015). This is supposed to be due to the
interaction of κ-opioid receptors with the dopamine system. In particular, it has been
shown that κ-agonists increase the extracellular dopamine concentration by an as yet
unclear mechanism (. Table 5.1).
Chapter 5 · GPCRs as Targets for Plant-Derived Drugs