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

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 ±â€¯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.

Chronic Compression of the Dorsal Root Ganglion Enhances Mechanically Evoked Pain Behavior and the Activity of Cutaneous Nociceptors in Mice.

Radicular pain in humans is usually caused by intraforaminal stenosis and other diseases affecting the spinal nerve, root, or dorsal root ganglion (DRG). Previous studies discovered that a chronic compression of the DRG (CCD) induced mechanical allodynia in rats and mice, with enhanced excitability of DRG neurons. We investigated whether CCD altered the pain-like behavior and also the responses of cutaneous nociceptors with unmyelinated axons (C-fibers) to a normally aversive punctate mechanical stimulus delivered to the hairy skin of the hind limb of the mouse. The incidence of a foot shaking evoked by indentation of the dorsum of foot with an aversive von Frey filament (tip diameter 200 µm, bending force 20 mN) was significantly higher in the foot ipsilateral to the CCD surgery as compared to the contralateral side on post-operative days 2 to 8. Mechanically-evoked action potentials were electrophysiologically recorded from the L3 DRG, in vivo, from cell bodies visually identified as expressing a transgenically labeled fluorescent marker (neurons expressing either the receptor MrgprA3 or MrgprD). After CCD, 26.7% of MrgprA3+ and 32.1% MrgprD+ neurons exhibited spontaneous activity (SA), while none of the unoperated control neurons had SA. MrgprA3+ and MrgprD+ neurons in the compressed DRG exhibited, in comparison with neurons from unoperated control mice, an increased response to the punctate mechanical stimuli for each force applied (6, 20, 40, and 80 mN). We conclude that CCD produced both a behavioral hyperalgesia and an enhanced response of cutaneous C-nociceptors to aversive punctate mechanical stimuli.

Psychophysical measurements of itch and nociceptive sensations in an experimental model of allergic contact dermatitis.

UNLABELLED: Allergic contact dermatitis (ACD) is a common condition that can significantly affect the quality of life. Contact with allergens results in delayed hypersensitivity reactions involving T lymphocytes, with associated skin inflammation and spontaneous itch and nociceptive sensations. However, psychophysical studies of these sensations are lacking. In the present study, we sensitized 8 healthy volunteers to squaric acid dibutyl ester (SADBE). Two weeks later, 1 volar forearm was challenged with SADBE, and the other with acetone vehicle control. Subsequently, participants rated the maximal perceived intensity of spontaneous itch, pricking/stinging, and burning every 6 to 12 hours for 1 week, using the generalized Labeled Magnitude Scale. In the laboratory, they judged stimulus-evoked sensations within and outside the chemically treated area. The SADBE- but not the acetone-treated skin resulted in 1) localized inflammation, with spontaneous itch and nociceptive sensations peaking at 24 to 48 hours after challenge, 2) alloknesis, hyperknesis, and hyperalgesia to mechanical stimuli that were reduced or eliminated by anesthetic cooling of the SADBE-treated area and restored on rewarming, suggesting that sensations and dysesthesias are dependent on ongoing peripheral neural activity, and 3) enhanced itch to intradermal injection of histamine, BAM8-22, or ß-alanine. This experimental model of T-cell-mediated inflammation may prove useful in evaluating potential treatments of itch from ACD. PERSPECTIVE: In a model of allergic contact dermatitis, experimentally applied in humans, psychophysical measurements were obtained of persistent, spontaneous itch and enhanced stimulus-evoked itch and pain sensations. These sensory measurements will be useful in the identification of the neural mechanisms underlying inflammatory itch and pain.