Involvement of the N/OFQ-NOP system in rat morphine antinociceptive tolerance: Are astrocytes the crossroad?

Abstract

The development of tolerance to the antinociceptive effect is a main problem associated with the repeated administration of opioids. The progressively higher doses required to relieve pain reduce safety and exacerbate the side effects of classical opioid receptor agonists like morphine. Nociceptin/orphanin FQ (N/OFQ) and its NOP receptor constitute the fourth endogenous opioid system that is involved in the control of broad spectrum of biological functions, including pain transmission. Aim of this work was to evaluate the relevance of the N/OFQ-NOP system in morphine antinociceptive action and in the development of morphine tolerance in the rat. Continuous spinal intrathecal infusion of morphine (1 – 3 nmol/h) evoked analgesic effects for 5 days in wild type animals. The same doses infused in NOP(−/−) rats showed a lower analgesic efficacy, while the onset of tolerance was delayed to day 9. N/OFQ (1 – 3 nmol/h), continuously infused in NOP(+/+) animals, showed an analgesic profile similar to morphine. Immunohistochemical analysis of the dorsal horn of the spinal cord of morphine tolerant NOP(+/+) rats showed an increased number of Iba1- and GFAP-positive cells (microglia and astrocytes, respectively). Interestingly, microglia but not astrocyte activation was observed in NOP(−/−) morphine tolerant rat. A selective activation of astrocytes was observed in the dorsal horn of wild type N/OFQ tolerant rats. The antinociceptive effect of morphine partially depends by the N/OFQ-NOP system that participates in the development of morphine tolerance. In particular, NOP receptors are involved in morphine-induced astrocyte activation, and N/OFQ per se increases astrocyte density.

Opioid Receptors in Immune and Glial Cells—Implications for Pain Control

“…Agonists of DOP and KOP receptors have not been tested. One study found elevated expression of astrocytes, but not microglia, in the spinal cord following N/OFQ treatment (142).…”

“…Furthermore, except for Chang et al (141) who used postoperative pain model, all other studies exclusively tested naïve mice or rats. Additionally, opioids were used at unconventional ultra-low doses or high doses which exceeded the analgesic doses used in pathological pain models, they were sometimes injected repetitively every few minutes, and hyperalgesia was measured 12 h, 24 h or 4 days following the last dose, which indicates opioid withdrawal-induced hyperalgesia (95,105,(135)(136)(137)(138)(139)(140)(141)(142). Therefore, these effects can be viewed in the context of dependence rather than pain management, which is in line with clinical findings [reviewed by (134,145)].…”

Spinal heat shock protein 27 participates in PDGFRβ‐mediated morphine tolerance through PI3K/Akt and p38 MAPK signalling pathways

“…HSP27 might also be transported from the perisynaptic glial processes to the postsynaptic elements (Bechtold & Brown, 2000). Astrocytes could play important roles in morphine tolerance (Micheli et al, 2018).…”

“…HSP27 might also be transported from the perisynaptic glial processes to the postsynaptic elements (Bechtold & Brown, 2000). Astrocytes could play important roles in morphine tolerance (Micheli et al, 2018). Our previous study demonstrated crosstalk between astrocytes and neurons in morphine tolerance (Guo et al, 2017).…”

MiR-140-5p inhibits morphine tolerance in rats by targeting TLR4

“…There is increasing evidence that morphine tolerance is a complex process. Currently, studies on the mechanisms of morphine tolerance are not limited to neurons; intraperitoneal injection of morphine can lead to significant morphine tolerance, while causing significant hypertrophy of astrocytes in the spinal cord as well as in the hippocampus [2]. Nonetheless, the specific mechanisms of morphine resistance remain to be further investigated [3].…”