Pharmacological Chaperones Attenuate the Development of Opioid Tolerance.

Opioids are potent analgesics widely used to control acute and chronic pain, but long-term use induces tolerance that reduces their effectiveness. Opioids such as morphine bind to mu opioid receptors (MORs), and several downstream signaling pathways are capable of inducing tolerance. We previously reported that signaling from the endoplasmic reticulum (ER) contributed to the development of morphine tolerance. Accumulation of misfolded proteins in the ER induced the unfolded protein response (UPR) that causes diverse pathological conditions. We examined the effects of pharmacological chaperones that alleviate ER stress on opioid tolerance development by assessing thermal nociception in mice. Pharmacological chaperones such as tauroursodeoxycholic acid and 4-phenylbutyrate suppressed the development of morphine tolerance and restored analgesia. Chaperones alone did not cause analgesia. Although morphine administration induced analgesia when glycogen synthase kinase 3ß (GSK3ß) was in an inactive state due to serine 9 phosphorylation, repeated morphine administration suppressed this phosphorylation event. Co-administration of chaperones maintained the inactive state of GSK3ß. These results suggest that ER stress may facilitate morphine tolerance due to intracellular crosstalk between the UPR and MOR signaling. Pharmacological chaperones may be useful in the management of opioid misuse.

Conflicting Actions of Inhalational Anesthetics, Neurotoxicity and Neuroprotection, Mediated by the Unfolded Protein Response.

Preclinical studies have shown that exposure of the developing brain to inhalational anesthetics can cause neurotoxicity. However, other studies have claimed that anesthetics can exert neuroprotective effects. We investigated the mechanisms associated with the neurotoxic and neuroprotective effects exerted by inhalational anesthetics. Neuroblastoma cells were exposed to sevoflurane and then cultured in 1% oxygen. We evaluated the expression of proteins related to the unfolded protein response (UPR). Next, we exposed adult mice in which binding immunoglobulin protein (BiP) had been mutated, and wild-type mice, to sevoflurane, and evaluated their cognitive function. We compared our results to those from our previous study in which mice were exposed to sevoflurane at the fetal stage. Pre-exposure to sevoflurane reduced the expression of CHOP in neuroblastoma cells exposed to hypoxia. Anesthetic pre-exposure also significantly improved the cognitive function of adult wild-type mice, but not the mutant mice. In contrast, mice exposed to anesthetics during the fetal stage showed cognitive impairment. Our data indicate that exposure to inhalational anesthetics causes endoplasmic reticulum (ER) stress, and subsequently leads to an adaptive response, the UPR. This response may enhance the capacity of cells to adapt to injuries and improve neuronal function in adult mice, but not in developing mice.

Pathogenic Effects of Impaired Retrieval between the Endoplasmic Reticulum and Golgi Complex.

Cellular activities, such as growth and secretion, are dependent on correct protein folding and intracellular protein transport. Injury, like ischemia, malnutrition, and invasion of toxic substances, affect the folding environment in the endoplasmic reticulum (ER). The ER senses this information, following which cells adapt their response to varied situations through the unfolded protein response. Activation of the KDEL receptor, resulting from the secretion from the ER of chaperones containing the KDEL sequence, plays an important role in this adaptation. The KDEL receptor was initially shown to be necessary for the retention of KDEL sequence-containing proteins in the ER. However, it has become clear that the activated KDEL receptor also regulates bidirectional transport between the ER and the Golgi complex, as well as from the Golgi to the secretory pathway. In addition, it has been suggested that the signal for KDEL receptor activation may also affect several other cellular activities. In this review, we discuss KDEL receptor-mediated bidirectional transport and signaling and describe disease models and human diseases related to KDEL receptor dysfunction.

Effects of Intraoperative Opioid Administration on Postoperative Pain and Pain Threshold: A Randomized Controlled Study.

Fentanyl and short-acting remifentanil are often used in combination. We evaluated the effect of intraoperative opioid administration on postoperative pain and pain thresholds when the two drugs were used. Patients who underwent gynecological laparoscopic surgery were randomly assigned into two groups (15 patients each) to receive either sufficient (group A) or minimum (group B) fentanyl (maximum estimated effect site concentration: A: 7.86 ng/mL, B: 1.5 ng/mL). The estimated effect site concentration at the end of surgery was adjusted to the same level (1 ng/mL). Patients in both groups also received continuous intravenous remifentanil during surgery. The primary outcome was the pressure pain threshold, as evaluated by a pressure algometer 3 h postoperatively. The pressure pain threshold at 3 h postoperatively was 51.1% (95% CI: [44.4-57.8]) in group A and 56.6% [49.5-63.6] in group B, assuming a preoperative value of 100% (p = 0.298). There were no significant differences in pressure pain threshold and numeric rating scale scores between the groups after surgery. The pain threshold decreased significantly in both groups at 3 h postoperatively compared to preoperative values, and recovered at 24 h. Co-administration of both opioids caused hyperalgesia regardless of fentanyl dose.