Introduction: We explored in mice, the analgesic, tolerance, dependency, and rewarding effects of systemic acetaminophen (APAP).
Methods: Studies employed adult mice (C57Bl6). (1) .
Background: A bioactive myelin basic protein (MBP) fragment, comprising MBP, is released in sciatic nerve after chronic constriction injury (CCI). Intraneural injection (IN) of MBP in an intact sciatic nerve is sufficient to induce persistent neuropathic pain-like behavior via robust transcriptional remodeling at the injection site and ipsilateral dorsal root ganglia (DRG) and spinal cord. The sex (female)-specific pronociceptive activity of MBP associates with sex-specific changes in cholesterol metabolism and activation of estrogen receptor (ESR)1 signaling.
View Article and Find Full Text PDFPain is the primary motivation for seeking medical care. Although pain may subside as inflammation resolves or an injury heals, it is increasingly evident that persistency of the pain state can occur with significant regularity. Chronic pain requires aggressive management to minimize its physiological consequences and diminish its impact on quality of life.
View Article and Find Full Text PDFIn the peripheral nerve, mechanosensitive axons are insulated by myelin, a multilamellar membrane formed by Schwann cells. Here, we offer first evidence that a myelin degradation product induces mechanical hypersensitivity and global transcriptomics changes in a sex-specific manner. Focusing on downstream signaling events of the functionally active 84-104 myelin basic protein (MBP(84-104)) fragment released after nerve injury, we demonstrate that exposing the sciatic nerve to MBP(84-104) via endoneurial injection produces robust mechanical hypersensitivity in female, but not in male, mice.
View Article and Find Full Text PDFBackground: We determined whether intrathecally delivering the same daily dose of morphine (MS) at a fixed concentration of 25 mg/mL by periodic boluses versus continuous infusion would reduce intrathecal mass (IMs) formation in dogs.
Methods: Adult dogs (hound cross, n = 32) were implanted with intrathecal catheters connected to SynchroMed II infusion pumps. Animals were randomly assigned to receive infusion of 0.
Objectives: DMT-DALDA (H-Dmt-D-Arg-Phe-Lys-NH2; Dmt = 2',6'-dimethyltyrosine) is a selective mu opioid agonist. We sought to characterize efficacy, tolerance, dependence and side-effect profile when given by continuous intrathecal infusion.
Materials And Methods: Adult male Sprague Dawley rats were prepared with chronic intrathecal catheters and osmotic mini-pumps to deliver vehicle (saline), DMT-DALDA or morphine.
Background and aims We systematically characterized the potency and side effect profile of a series of small opioid peptides with high affinity for the mu opioid receptor. Methods Male Sprague Dawley rats were prepared with intrathecal (IT) catheters, assessed with hind paw thermal escape and evaluated for side effects including Straub tail, truncal rigidity, and pinnae and corneal reflexes. In these studies, DMT-DALDA (dDAL) (H-Dmt-D-Arg-Phe-Lys-NH2 MW=981), dDALc (H-Dmt-Cit-Phe-Lys-NH2 MW=868), dDALcn (H-Dmt-D-Cit-Phe-Nle-NH2 MW=739), TAPP (H-Tyr-D-Ala-Phe-Phe-NH2 MW=659), dDAL-TICP ([Dmt1]DALDA-(CH2)2-NH-TICP[psi]; MW=1519), and dDAL-TIPP (H-Dmt-D-Arg-Phe-Lys(Nε-TIPP)-NH2 were examined.
View Article and Find Full Text PDFNeurogenic inflammation results from the release of biologically active agents from the peripheral primary afferent terminal. This release reflects the presence of releasable pools of active product and depolarization-exocytotic coupling mechanisms in the distal afferent terminal and serves to alter the physiologic function of innervated organ systems ranging from the skin and meninges to muscle, bone, and viscera. Aside from direct stimulation, this biologically important release from the peripheral afferent terminal can be initiated by antidromic activity arising from five anatomically distinct points of origin: (i) afferent collaterals at the peripheral-target organ level, (ii) afferent collaterals arising proximal to the target organ, (iii) from mid-axon where afferents lacking myelin sheaths (C fibers and others following demyelinating injuries) may display crosstalk and respond to local irritation, (iv) the dorsal root ganglion itself, and (v) the central terminals of the afferent in the dorsal horn where local circuits and bulbospinal projections can initiate the so-called dorsal root reflexes, i.
View Article and Find Full Text PDFThe nervous system detects and interprets a variety of chemical, mechanical, and thermal stimuli. In the face of tissue injury, local inflammatory products perpetuate ongoing activity and sensitisation of the peripheral nerve termini. This ongoing activity evokes a state of robust spinal facilitation mediated by a number of local circuits, the net effect yielding an enhanced message of nociception to higher centres.
View Article and Find Full Text PDFBackground AYX1 is an unmodified DNA-decoy designed to reduce acute post-surgical pain and its chronification with a single intrathecal dose at the time of surgery. AYX1 inhibits the transcription factor early growth response protein 1, which is transiently induced at the time of injury and triggers gene regulation in the dorsal root ganglia and spinal cord that leads to long-term sensitization and pain. This work characterizes the AYX1 dose-response profile in rats and the link to AYX1 pharmacokinetics and metabolism in the cerebrospinal fluid, dorsal root ganglia, and spinal cord.
View Article and Find Full Text PDFBackground: Intrathecal infusion of opioids in dogs, sheep, and humans produces local space-occupying masses. To develop a small-animal model, the authors examined effects of intrathecal catheterization and morphine infusion in guinea pigs.
Methods: Under isoflurane, polyethylene or polyurethane catheters were advanced from the cisterna magna to the lumbar enlargement.
Objective: Pain resulting from local tissue injury or inflammation typically resolves with time. Frequently, however, this pain may unexpectedly persist, becoming a pathological chronic state. Increasingly, the innate and adaptive immune systems are being implicated in the initiation and maintenance of these persistent conditions.
View Article and Find Full Text PDFMechanosensory fibers are enveloped by myelin, a unique multilamellar membrane permitting saltatory neuronal conduction. Damage to myelin is thought to contribute to severe pain evoked by innocuous tactile stimulation (i.e.
View Article and Find Full Text PDFWe addressed the hypothesis that intraplantar botulinum toxin B (rimabotulinumtoxin B: BoNT-B) has an early local effect upon peripheral afferent terminal releasing function and, over time, will be transported to the central terminals of the primary afferent. Once in the terminals it will cleave synaptic protein, block spinal afferent transmitter release, and thereby prevent spinal nociceptive excitation and behavior. In mice, C57Bl/6 males, intraplantar BoNT-B (1 U) given unilaterally into the hind paw had no effect upon survival or motor function, but ipsilaterally decreased: (1) intraplantar formalin-evoked flinching; (2) intraplantar capsaicin-evoked plasma extravasation in the hind paw measured by Evans blue in the paw; (3) intraplantar formalin-evoked dorsal horn substance P (SP) release (neurokinin 1 [NK1] receptor internalization); (4) intraplantar formalin-evoked dorsal horn neuronal activation (c-fos); (5) ipsilateral dorsal root ganglion (DRG) vesicle-associated membrane protein (VAMP); (6) ipsilateral SP release otherwise evoked bilaterally by intrathecal capsaicin; (7) ipsilateral activation of c-fos otherwise evoked bilaterally by intrathecal SP.
View Article and Find Full Text PDFBackground: Spinal Toll-like receptors (TLRs) and signaling intermediaries have been implicated in persistent pain states. We examined the roles of two major TLR signaling pathways and selected TLRs in a mononeuropathic allodynia.
Methods: L5 spinal nerve ligation (SNL) was performed in wild type (WT, C57BL/6) male and female mice and in male Tlr2-/-Tlr3-/-, Tlr4-/-, Tlr5-/-, Myd88-/-, Triflps2, Myd88/Triflps2, Tnf-/-, and Ifnar1-/- mice.