Functional and Histopathological Neurotoxicity of Microsphere-Based Bupivacaine in a Rat Sciatic Nerve Blockade Model
1China Medical University Beigang Hospital Anaesthesiology Department, Yunlin, Taiwan.
Background:
The novel extended-release formulation of microsphere-based bupivacaine (MBB) has demonstrated a dose-dependent pharmacodynamic efficacy in the rat neuropathic pain model. This longitudinal, sham-operated control study evaluated its long-term neurotoxicity profile under functional and histopathological quantification in a rat sciatic nerve block model.
Methods:
Twenty-eight Sprague-Dawley rats underwent skin incision and muscle separation to expose the sciatic nerve at both mid-thigh levels. A catheter was then implanted adjacent to the left sciatic nerve. Following a smooth recovery on postoperative day 7, 1.5 mL of 50 mg/kg MBB was injected through the catheter. Meanwhile, Rotarod, hotplate, and von Frey fi lament tests were then assessed before and 7 days after injection to test the functional neurotoxicity with respect to the sensory and motor impairment. Rats were sacrificed for serial histopathological examination on post-injection D7 (day 7) (n = 8), D14 (day 14) (n = 8), and D28 (day 28) (n = 12).
Results:
There were no significant histopathologic changes in the sciatic nerve and muscles of the sham-operated rats. Rotarod, hotplate, and von Frey filament tests were comparable at D0 and D7. MBB induced a transient and mild inflammatory reaction in the neural tissues, which completely resolved by D14. On D7 post-administration, moderate to severe infiltration of mononuclear cells and accumulation of multinucleated giant cells and neutrophils. Quantification of the improvement rate significantly improved from 40% on D7 to 70% by D28.
Conclusion:
Our histopathological and behavioral studies demonstrated that injecting a single dose of 50 mg/kg MBB over the sciatic nerve trunk exhibited transient but mild neurotoxicity and more profound myotoxicity. Serial sections indicated a trend toward resolution over a 28-day span, although most rats still exhibited slight to mild inflammation in the muscular tissue, presumably due to the catheter in situ, which recovered 4 weeks later.
Insights
Microsphere-based bupivacaine (MBB) showed mild, temporary neurotoxicity and myotoxicity in rats. Full recovery was observed within 28 days, indicating a favorable safety profile for this extended-release formulation.
Area of Science:
- Neuroscience
- Pharmacology
- Biomaterials Science
Background:
- Microsphere-based bupivacaine (MBB) is an extended-release formulation with demonstrated efficacy in neuropathic pain models.
- Previous studies indicated dose-dependent pharmacodynamic effects in rat models.
- This study aimed to assess the long-term neurotoxicity of MBB.
Purpose of the Study:
- To evaluate the long-term neurotoxicity profile of microsphere-based bupivacaine (MBB).
- To quantify functional and histopathological changes following sciatic nerve block in rats.
- To assess the safety of MBB in a preclinical animal model.
Main Methods:
- Sciatic nerve exposure and catheter implantation in Sprague-Dawley rats.
- Single injection of 50 mg/kg MBB via catheter.
- Functional neurotoxicity assessment using Rotarod, hotplate, and von Frey filament tests.
- Histopathological examination of neural and muscle tissues at 7, 14, and 28 days post-injection.
Main Results:
- No significant histopathologic changes were observed in sham-operated control rats.
- MBB induced a transient, mild inflammatory reaction in neural tissues, resolving by day 14.
- Moderate to severe mononuclear cell infiltration and giant cell accumulation occurred on day 7, with significant improvement by day 28.
- Functional tests showed transient sensory and motor impairment, with significant recovery observed over the 28-day period.
Conclusions:
- A single 50 mg/kg dose of MBB via sciatic nerve injection resulted in transient, mild neurotoxicity and more pronounced myotoxicity.
- Histopathological and behavioral studies indicated a trend toward resolution of effects within 28 days.
- Residual mild inflammation in muscle tissue was noted, potentially related to the indwelling catheter, with recovery observed by 4 weeks post-injection.
