On the g-protein-coupled receptor heteromers and their allosteric receptor-receptor interactions in the central nervous system: focus on their role in pain modulation

Abstract

The modulatory role of allosteric receptor-receptor interactions in the pain pathways of the Central Nervous System and the peripheral nociceptors has become of increasing interest. As integrators of nociceptive and antinociceptive wiring and volume transmission signals, with a major role for the opioid receptor heteromers, they likely have an important role in the pain circuits and may be involved in acupuncture. The delta opioid receptor (DOR) exerts an antagonistic allosteric influence on the mu opioid receptor (MOR) function in a MOR-DOR heteromer. This heteromer contributes to morphine-induced tolerance and dependence, since it becomes abundant and develops a reduced G-protein-coupling with reduced signaling mainly operating via β -arrestin2 upon chronic morphine treatment. A DOR antagonist causes a return of the Gi/o binding and coupling to the heteromer and the biological actions of morphine. The gender- and ovarian steroid-dependent recruitment of spinal cord MOR/kappa opioid receptor (KOR) heterodimers enhances antinociceptive functions and if impaired could contribute to chronic pain states in women. MOR1D heterodimerizes with gastrin-releasing peptide receptor (GRPR) in the spinal cord, mediating morphine induced itch. Other mechanism for the antinociceptive actions of acupuncture along meridians may be that it enhances the cross-desensitization of the TRPA1 (chemical nociceptor)-TRPV1 (capsaicin receptor) heteromeric channel complexes within the nociceptor terminals located along these meridians. Selective ionotropic cannabinoids may also produce cross-desensitization of the TRPA1-TRPV1 heteromeric nociceptor channels by being negative allosteric modulators of these channels leading to antinociception and antihyperalgesia.

Figure 1

Pain pathways and their regulation through WT and VT signals integrated through receptor-receptor interactions in heteromers. (left) A schematic overview of the ascending main circuits mediating pain. When a noxious stimulus is encountered. Afferent nociceptors convey noxious information to projection neurons within the dorsal horn of the spinal cord. Neurotransmitters released here bind to and activate postsynaptic receptors on pain transmission neurons. In turn, the axons of pain transmission neurons ascend, predominantly contralaterally, to the brain and carry the information about the noxious stimulus to higher centers (somatosensory cortex via the thalamus with information about location and intensity of the painful stimulus or the insular cortices via connections in the brainstem (parabranchial nucleus) and amygdala within the affective component of the pain experience). The descending inhibitory pathways to the dorsal horn from the brainstem involving interalia the NA, 5HT, and DA pathways (see text) are also indicated. They exert antinociceptive actions in the pain circuits of the dorsal horn. (right) The diagram shows a few prominent of many possible mediators and cell-cell interactions in the spinal cord dorsal horn, thalamus, or amygdala. In these pain circuits opioid receptor containing heteromers may play a role in the modulation of pain transmission, offering novel targets for antinociceptive drugs. The enkephalin peptides (short distance diffusion) and b-endorphin (long distance diffusion) mainly operate via VT and likely modulate the pain circuits via receptor-receptor interactions in receptor heteromers built-up of synaptic protomers and of opioid receptor protomers. In this way synaptic transmission signals and VT signals become integrated giving a balance in nociceptive and antinociceptive signaling in the CNS. The descending inhibitory pathways to the dorsal horn involving inter alia the monoamine pathways also mainly communicate via VT (see text).

Figure 2

Intra- and intermolecular allosteric receptor-receptor interactions. Allosteric mechanisms make possible the integrative activity taking place intramolecularly in monomers (left) or intermolecularly in homo-/heteromers (right). As one example of the intramolecular allosteric mechanisms is the allosteric binding of salvinorin A to the extracellular site of MOR, which partially affects the activity of the orthosteric MOR binding site via a conformational change [105]. Intermolecular allosteric mechanisms take place through the formation of different types of receptor homo-/heteromers and receptor/protein complexes which can change the function of an individual receptor present in a homomer or heteromer. Another example based on the intermolecular heteromer interactions is the use of heterobivalent ligands containing a MOR agonist and an DOR antagonist linked through a spacer of variable size which may function as useful molecular probes for targeting the MOR-DOR heteromer and in this way counteracting the DOR antagonism on MOR function. Such compounds may have a potential use in pharmacotherapy of pain.

Figure 3

Receptor-receptor interactions in different types of opioid receptor heteromers in the CNS and their potential role in pharmacotherapy of pain. The homo- and heterodimers would allow direct physical interactions between the receptors making possible the allosteric receptor receptor interactions between them. The functional balance between these oligomers determines the final functional output and thus the eventual cellular response. The schematic representation depicts some of the principal, nonexclusive, molecular mechanisms by which opioid heteromers produce novel functions.