Polyglycerol-opioid conjugate produces analgesia devoid of side effects

Abstract

Novel painkillers are urgently needed. The activation of opioid receptors in peripheral inflamed tissue can reduce pain without central adverse effects such as sedation, apnoea, or addiction. Here, we use an unprecedented strategy and report the synthesis and analgesic efficacy of the standard opioid morphine covalently attached to hyperbranched polyglycerol (PG-M) by a cleavable linker. With its high-molecular weight and hydrophilicity, this conjugate is designed to selectively release morphine in injured tissue and to prevent blood-brain barrier permeation. In contrast to conventional morphine, intravenous PG-M exclusively activated peripheral opioid receptors to produce analgesia in inflamed rat paws without major side effects such as sedation or constipation. Concentrations of morphine in the brain, blood, paw tissue, and in vitro confirmed the selective release of morphine in the inflamed milieu. Thus, PG-M may serve as prototype of a peripherally restricted opioid formulation designed to forego central and intestinal side effects.DOI: http://dx.doi.org/10.7554/eLife.27081.001

Opioid receptor signaling, analgesic and side effects induced by a computationally designed pH-dependent agonist

“…HEK293 cells stably expressing rat MOR were cultured in flasks with a growth area of 175 cm². Cells were washed twice with ice-cold assay buffer (Trizma® Preset Crystals, 50 mM, pH 7.4) (Sigma-Aldrich), then scratched from the culture flask in 10 ml ice cold assay buffer, homogenized and centrifuged twice at 42,000 g for 20 min at 4 °C as described previously 7 , 19 , 20 . Protein concentration was determined according to the Bradford method 21 .…”

“…A protein amount of 80–100 µg was incubated with 4 nM [ 3 H]-DAMGO (50 Ci/mmol) and FF3 dissolved in 50 mM assay buffer at pH 6.5 or 7.4 for 90 min at room temperature. Nonspecific binding was determined by the addition of 10 µM NLX 20 . Filters were soaked in 0.1% polyethyleneimine solution before use.…”

Analgesic effects of a novel pH-dependent μ-opioid receptor agonist in models of neuropathic and abdominal pain

“… 33 Targeting peripheral opioid receptors in damaged tissue avoids adverse opioid effects in the brain or gut, as well as detrimental side effects of NSAIDs, as demonstrated in animal models and humans with acute and chronic pain. 11 , 29 , 32 , 33 , 37 , 41 Moreover, pharmacological, genetic, and clinical studies have shown that a large proportion of opioid analgesia is mediated by peripheral opioid receptors 10 , 15 , 39 and that such receptors can confer significant anti-inflammatory effects. 34 …”

Tailor‐Made Core‐Multishell Nanocarriers for the Delivery of Cationic Analgesics to Inflamed Tissue

“…[39,42] The paw pressure threshold (cut-off at 250 g) required to elicit paw withdrawal was determined by averaging three consecutive trials separated by 15-s intervals. [39,42] The paw pressure threshold (cut-off at 250 g) required to elicit paw withdrawal was determined by averaging three consecutive trials separated by 15-s intervals.…”

“…In Figure 4 the release of U50 from either of the four nanocarrier architectures or as a mesylate salt is depicted. [41][42][43] Without any carrier (black and blue curves, Figure 5, left and right) there was no difference between pH 7.4 and 5.5. Compared to that, the release from CMS-A only seemed to feature a weak retention effect, as the blue curve (Figure 4, right) did not differ from the black one very strongly and the error bars partially overlapped.…”