RGS9 proteins facilitate acute tolerance to mu‐opioid effects

Abstract

This paper reports that regulators of G‐protein signalling (RGS) proteins modulate the timing and amplitude of opioid signals by a push–pull mechanism. This is achieved without noticeable changes in the binding properties of opioids, e.g. β‐endorphin to mu‐opioid receptors. The expression of RGS proteins was reduced by blocking their mRNA with antisense oligodeoxynucleotides (ODN). Knock down of RGS2 or RGS3 diminished morphine and β‐endorphin analgesia, whereas that of RGS9 or RGS12 enhanced this activity. In mice with impaired RGS9, but not impaired RGS2, the potency and, in particular, the duration of opioid antinociception increased. Further, the animals did not exhibit acute tolerance generated by a single and efficacious dose of morphine, nor did they develop tolerance after a daily i.c.v. injection of the opioid for 4 days. In a model of sustained morphine treatment, the impairment of RGS9 proteins facilitated increases in the response to the delivered opioid. This was only effective for 2–3 h after the subcutaneous implantation of an oily morphine pellet; later, tolerance developed. To reduce the impact of the chronic morphine acting on opioid receptors, other RGS proteins presumably substitute the GTPase‐activating function of RGS9 on morphine‐activated Gα‐GTP subunits. The desensitization of mu‐opioid receptors appears to be a cell membrane‐limited process facilitated by RGS9′s sequestering of agonist‐segregated Gα subunits.

Endogenous RGS Protein Action Modulates μ-Opioid Signaling through Gαo

“…In support of this idea, overexpression of RGS2 shifts the concentration effect curve for morphine-stimulated pigment aggregation to the right to a small (2-fold) degree in cultured dermal melanophores from Xenopus laevis transiently expressing a murine -opioid receptor (9). Furthermore, a reduction in RGS9 levels in mice using antisense oligonucleotide leads to an increase in the anti-nociceptive potency of morphine (10). Although these changes are small, they are suggestive of a role for RGS proteins in opioid coupling efficiency.…”

Expression changes in arrestin β 1 and genetic variation in catechol-O-methyltransferase are biomarkers for the response to morphine treatment in cancer patients

“…Agonists for opioid receptors induce the activation of GPCRs, triggering the activ ation of various downstream molecules (2). A regulator of the G-protein signaling (RGS)-protein family negatively regulates opioid-receptor signaling by accelerating the deactivation of G proteins, and the regulators RGS2 and RGS9 are thought to be involved in resistance to morphine (4)(5)(6). In addition, G-protein coupled receptor kinase (GRK) phosphorylates the opioid receptors, leading to the binding of arrestin β 1 and 2 (ARRB1 and 2) to the opioid receptors (7).…”

Activation of μ-Opioid Receptors Transfers Control of Gα Subunits to the Regulator of G-protein Signaling RGS9-2

“…In the central nervous system, MORs play an important role in the antinociceptive action of opioids, but they become desensitized after repeated administration. Such tolerance is observed even after a single dose of an opioid agonist and can persist for ϳ3 days (6,7). This common characteristic of opioids that act via MORs is a serious drawback with respect to their long-term use as analgesics for the treatment of chronic pain.…”

“…The RGS-R7 proteins show negative regulatory activity on the intensity of signals originating at MORs; thus, they participate in the development of tolerance to ago-nist effects (21,22). RGS9-2 is particularly important with respect to this function because its impairment provokes an increase in the potency of -opioid agonists and prevents (or at least delays) the appearance of MOR desensitization (7,21,23).…”