Chronic morphine exposure potentiates p-glycoprotein trafficking from nuclear reservoirs in cortical rat brain microvessels

Abstract

The rates of opioid prescription and use have continued to increase over the last few decades resulting in a greater number of opioid tolerant patients. Treatment of acute pain from surgery and injury is a clinical challenge for these patients. Several pain management strategies including prescribing increased opioids are used clinically with limited success; all currently available strategies have significant limitations. Many opioids are a substrate for p-glycoprotein (p-gp), an efflux transporter at the blood-brain barrier (BBB). Increased p-gp is associated with a decreased central nervous system uptake and analgesic efficacy of morphine. Our laboratory previously found that acute peripheral inflammatory pain (PIP) induces p-gp trafficking from the nucleus to the luminal surface of endothelial cells making up the BBB concomitant with increased p-gp activity and decreased morphine analgesic efficacy. In the current study, we tested whether PIP-induced p-gp trafficking could contribute to decreased opioid efficacy in morphine tolerant rats. A 6-day continuous dosing of morphine from osmotic minipumps was used to establish morphine tolerance in female rats. PIP induced p-gp trafficking away from nuclear stores showed a 2-fold increase in morphine tolerant rats. This observation suggests that p-gp trafficking contributes to the decreased morphine analgesic effects in morphine tolerant rats experiencing an acute pain stimulus. Attenuating p-gp trafficking during an acute pain stimulus could improve pain management by increasing the amount of opioid that could reach CNS analgesic targets and decrease the need for the dose escalation that is a serious challenge in pain management.

Mitragynine Attenuates Morphine Withdrawal Effects in Rats—A Comparison With Methadone and Buprenorphine

“…Various methods have been established to model morphine withdrawal in rats including implantation of morphine pellet (55, 56, 69-71), infusion method via implantation of intravenous catheters (72,73), subcutaneous mini osmatic pumps (74,75), drinking morphine solution containing water or sucrose (76)(77)(78), morphine-admixed food (79), or subcutaneous injection (80)(81)(82)(83) and intraperitoneal route (54, 84,85). However, all these methods have certain disadvantages.…”

P-Glycoprotein/ABCB1 Might Contribute to Morphine/Cisplatin-Induced Hepatotoxicity in Rats

“…The combined effect of MOR and CP was even further increase in hepatic P-gp level in the current study. Previous studies investigated the effect of MOR and/or CP on P-gp expression in the blood-brain barrier [37][38][39], and reported that both CP and MOR might up-regulate P-gp in this sanctuary barrier, causing efflux of the latter and decrease in its central penetration, and consequently, decrease in its analgesic efficacy. Up-regulation of P-gp by CP was not reported to be limited to normal body cells, but extended to include tumor cells [33], where P-gp was related to MDR of cancer cells against chemotherapeutic [40], especially when using P-gp substrates as anticancer drugs concomitantly with CP.…”

Purified IgG from aquaporin-4 neuromyelitis optica spectrum disorder patients alters blood-brain barrier permeability

“…In order to study the impact of NMO-IgG on BBB structure itself, we use an original ex vivo BBB mimicking the close relationship between NMO-IgG and brain microvessels. Fresh IBM are known to maintain in vivo BBB properties, and have been previously used for the study of endothelial molecular transporters [31,32], drug pharmacokinetic or pharmacodynamics [33], and disease pathophysiology in animal models [34,35]. However, the application of this technique on NMOSD-related models has not been previously performed.…”