Background & Aims
Chronic neuropathic pain is maintained in part by spinal excitatory signaling and increased glutamate receptor activity contributing to central sensitization. Glutamate receptor antagonists, like the metabotropic glutamate receptor 5 (mGLUR5) antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP), can be analgesic after neuropathic injury [1-5]. But, its clinical use is limited because of its high dosing, risk for toxicity, and substantial side effects [6-9]. Animal studies demonstrate analgesic effectiveness of MPEP at low doses for invasive and repeated delivery approaches [5,10]. MPEP is an ideal drug candidate for micelle delivery by which encapsulation can provide localized release and reduce off-target side effects at a lower overall dose [11,12]. This study aimed to improve the delivery of MPEP in vivo through encapsulation in PEG-PCL micelles and tested effectiveness in alleviating established pain and spinal neuronal hyperexcitability in a rodent model of nerve root compression.
Methods
MPEP micelles were prepared using an oil-in-water emulsion [13,14] from block copolymers mPEG(4K)-b-PCL(3K). Under isoflurane, male Holtzman rats underwent a painful nerve root compression [15-17]. On day 7 in separate groups, either loaded micelles containing an MPEP dose of 3mg/kg (n=5) or free MPEP at a dose of 30mg/kg (n=6) was administered intravenously by the tail vein. A third group received a comparable volume-matched dose of unloaded micelles (n=4) on day 7 as a vehicle control. A sham surgical procedure was administered in a separate group (n=6), with nerve root exposure only and a volume-matched dose of phosphate buffered saline (PBS) [15,18]. Ipsilateral forepaw withdrawal thresholds were measured using a modified Chaplan’s up-down method [13-16] before injury (day 0) and daily for 14 days. Evoked spinal neuronal recordings were made on day 14; differences in withdrawal thresholds and spike counts between groups were determined by ANOVA and Tukey’s tests.
Results
Intravenously administered MPEP-loaded micelles attenuated existing pain resulting in no difference in thresholds between that group and shams (p=0.84) and did so at a dose 10-times lower than the systemic administration of free MPEP. Further, the free MPEP had no effect on withdrawal thresholds, which remained significantly lower than those for sham (p<0.003) and at baseline (p<0.035). Treatment with the MPEP micelles also attenuated evoked (p<0.01) spinal neuronal hyperexcitability, as well as restored the relative distribution of spinal neurons (38.6% WDR, 49.1% LTM, 12.3% NS) to the distribution of neuronal phenotypes detected in sham (34.4% WDR, 46.8% LTM, 18.8% NS) rats (p=0.54). The distribution in the sham rats was also different from the distribution in the free MPEP (p=0.003) and unloaded micelle (p=0.03).
Conclusions
These findings indicate that micellar delivery of MPEP may be a potent treatment approach for established neuropathic pain and could be used to increase the effectiveness of other neuromodulatory drugs that are otherwise hindered by poor delivery. Further, these findings suggest that improving the delivery of neuromodulatory drugs by encapsulating them in micelles and/or other nanoformulations may present a method to increase their effectiveness in the clinic, providing pain relief at lower doses and/or with less frequent injections. While future studies will refine the formulation of MPEP loaded micelles, these studies suggest that MPEP-loaded micelles may be a potent delivery platform to treat persistent pain after neuropathic injury.
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Presenting Author
Beth A Winkelstein
Poster Authors
Topics
- Treatment/Management: Pharmacology: Non-opioid