Anti-nociceptive effects of bupivacaine-encapsulated PLGA nanoparticles applied to the compressed dorsal root ganglion in mice

Abstract

Bupivacaine is a commonly used local anesthetic in postoperative pain management. We evaluated the effects of a prolonged, local delivery of bupivacaine on pain behavior accompanying a chronic compression of the dorsal root ganglion (CCD) – an animal model of radicular pain. Poly(lactide-coglycolide) (PLGA) nanoparticles encapsulating bupivacaine were injected unilaterally into the L3 and L4 DRGs of mice just before producing CCD by implanting a stainless-steel rod in the intervertebral foramen of each ganglion. Behavioral sensitivity to punctate mechanical stimuli (Von Frey filaments) of different forces of indentation, delivered to each hind paw, was measured before and on subsequent days of testing after the CCD. Nanoparticles were spherical in morphology and 150 ± 10 nm in diameter. Bupivacaine was steadily released as measured in vitro over 35 days. A dye that was encapsulated in the nanoparticles was found in the intact DRG after 2 weeks. CCD alone or with injection of blank (control) nanoparticles produced a behavioral hypersensitivity to the punctate stimuli on the ipsilateral paw without affecting sensitivity on the contralateral, over a period of 7–14 days. The hypersensitivity was manifested as an increased incidence of paw-withdrawal to indentation forces normally below threshold (allodynia) and an increased shaking to a filament force that always elicited withdrawal prior to CCD (hyperalgesia). In contrast, nanoparticles with bupivacaine prevented any manifestation of allodynia or hyperalgesia on the ipsilateral hind paw while leaving normal nociceptive responses largely intact on both hind paws. CCD induced behavioral hypersensitivity to nociceptive stimuli is known to be associated with a hyperexcitability of sensory neurons originating in the compressed ganglion. We hypothesize that bupivacaine-loaded PLGA nanoparticles may prevent the occurrence of this neuronal hyperexcitability without reducing the nociceptive information normally conducted from the periphery to the central nervous system. The slow, sustained delivery of bupivacaine by nanoparticles may provide a means of preventing the occurrence of postoperative neuronal hyperexcitability that could develop into chronic neuropathic pain.