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Decreased release of neurotransmitters

Figure 1-45. The interaction of the opioid receptor with the potassium ion-channel, which after activation results in an increased outward shift of potassium resulting in a hyperpolarized state

Figure 1-46. Schematic representation of the dormant opioid receptor, a 7 helix transmembrane, G-protein-coupled receptor. Following binding, the intracellular mediator G-protein with its a-, 3- and ^-subunit is activated resulting in the decreased formation of cyclic AMP GDP-Guanidine dip

A secondary and important messenger of opioid action is G-protein, which after activation results in formation of guanidindiphosphate (GDP) to guanidintriphos-phate (GTP; Figures I-46 and I-47).

This transformational process, as a consequence, results in the dissociation of G-protein from the receptor and a reduction of affinity of the ligand. If this process lasts for a long period of time, it results in the development of tachyphylaxis. By dissociation of the a-GDP subunit from the remaining p/7-complex of G-protein,

cell membrane

cell membrane

Figure 1-47. Following binding of an opioid ligand to the receptor site, guanidine-diphosphate (GDP) is activated resulting in the formation of guanidine-triphosphate (GTP)

by means of enzyme phosphorylation of AC and a reduction in cAMP, it interacts with the effector site, a calcium/potassium-channel (Figure I-48). This results in permeability changes of the voltage-gated ion channel, with an inward shift of potassium, and an outward shift of calcium ions, resulting in hyperpolarization.

Such changes result in a reduced response to all incoming nociceptive afferents as the neuronal cell no longer can be depolarized. GTP releasing its phosphate constituent, results in the dissociation of the a-unit from G-protein, and ends opioid action. After merger of the a- with the remaining p/7-complex, the cell again returns into its dormant state. Such opioid-related analgesic effect first is initiated at the spinal cord level, where analgesics bind to opioid receptors. Via intraneuronal links a reduction in response of cellular reactions to all incoming nociceptive afferences is initiated. The spinal cord nerve cell no longer responds to subsequent afferent impulses from the periphery, no excitatory transmitters are being released at the synaptic cleft, interrupting nociceptive transmission.

The neuromolecular changes induced by opioids support the need for sufficient blockade of pain before nociceptive afferents arrive at the scene. Clinically, in the framework of anesthesia for example, such knowledge demands sufficient analgesia before a surgical intervention, as well as a prolonged postoperative and/or posttrau-matic pain relief with an opioid. These facts also demand a sufficient high dosage of a narcotic analgesic in order to bind all opioid existing receptors. Then the nociceptive impulse is effectively blocked by an opioid before arrival of nociceptive afferents. Instead of trying to cancel out an already started process of chronification

Figure I-48. The secondary intracellular messenger G-protein being activated after binding of a narcotic analgesic, resulting in a secondary transmembrane flux of electrolytes of voltage gated ion channels with hyperpolarization

and neuroplastic changes with higher doses than necessary, lesser doses are needed when opioid therapy is initiated before exposure to pain [23].

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