Opioid receptors have been demonstrated on sensory nerves in both inflamed and normal subcutaneous tissue but locally applied opioid agonists produce analgesia in inflamed tissue only. Inflammation confers a disruption of the perineurial barrier that can also be induced deliberately by hyperosmolar solutions. The present study examines at which stage of Freund's adjuvant-induced inflammation peripheral opioid analgesic effects become manifest and whether a perineurial defect contributes to the appearance of such effects. To this end we have monitored the temporal evolution of inflammatory signs (swelling, temperature, hyperalgesia) and of peripheral antinociceptive effects (by the paw pressure test) of mu-, delta-, and kappa-selective opioids. Using horseradish peroxidase histochemistry, the perineurial barrier was assessed in normal and inflamed tissue and following its artificial disruption by hyperosmolar saline and mannitol in vivo. Finally, we sought to elicit analgesia in normal tissue by the concomitant application of mannitol and receptor-selective opioids or by an extremely lipophilic opioid agonist (fentanyl). We found that peripheral opioid antinociception and perineurial leakage occur simultaneously at a very early stage (within 12 hr) of the inflammatory reaction and that both can be mimicked by the administration of hyperosmolar solutions in normal tissue. Fentanyl produced peripheral antinociception in noninflamed tissue that was potentiated by mannitol or inflammation. Our findings demonstrate that the perineurium is a crucial determinant for peripheral opioid analgesia and that the efficacy of locally applied hydrophilic or lipophilic neuromodulatory compounds can be improved dramatically by the concomitant modulation of perineurial permeability.(ABSTRACT TRUNCATED AT 250 WORDS)

https://www.jneurosci.org/content/jneuro/15/1/165.full.pdf

Perineurial defect and peripheral opioid analgesia in inflammation

The endoneurial microenvironment, delimited by the endothelium of endoneurial vessels and a multi-layered ensheathing perineurium, is a specialized milieu interieur within which axons, associated Schwann cells and other resident cells of peripheral nerves function. The endothelium and perineurium restricts as well as regulates exchange of material between the endoneurial microenvironment and the surrounding extracellular space and thus is more appropriately described as a blood–nerve interface (BNI) rather than a blood–nerve barrier (BNB). Input to and output from the endoneurial microenvironment occurs via blood–nerve exchange and convective endoneurial fluid flow driven by a proximo-distal hydrostatic pressure gradient. The independent regulation of the endothelial and perineurial components of the BNI during development, aging and in response to trauma is consistent with homeostatic regulation of the endoneurial microenvironment. Pathophysiological alterations of the endoneurium in experimental allergic neuritis (EAN), and diabetic and lead neuropathy are considered to be perturbations of endoneurial homeostasis. The interactions of Schwann cells, axons, macrophages, and mast cells via cell–cell and cell–matrix signaling regulate the permeability of this interface. A greater knowledge of the dynamic nature of tight junctions and the factors that induce and/or modulate these key elements of the BNI will increase our understanding of peripheral nerve disorders as well as stimulate the development of therapeutic strategies to treat these disorders.

/pdf/homeostatic-regulation-of-the-endoneurial-microenvironment-4i3us22zfd.pdf

Homeostatic regulation of the endoneurial microenvironment during development, aging and in response to trauma, disease and toxic insult

Animal models of diabetes mellitus: physiology and pathology.

Nerve regeneration across a 10-mm gap was delayed in streptozotocin diabetic rats 3 and 4 weeks after transecting the sciatic nerve. Opposite ends of each cut nerve were introduced into a silicone tube, leaving a 10-mm gap. Electron microscopy was used to evaluate the progress of regeneration in sections at 2-mm intervals across the 10-mm gap. After 3 weeks, control axons had bridged the 10-mm gap, and myelin sheaths extended for 6-8 mm. By contrast, axons and their myelin sheaths were seen no further than 2 mm from the proximal stump in diabetic animals. By 4 weeks, axons had bridged the gap in diabetics; however, they appeared immature and showed dystrophic changes. The findings suggest that although regeneration does occur in diabetic nerves, it is significantly delayed and qualitatively impaired.

Delayed nerve regeneration in streptozotocin diabetic rats

For about a hundred years, nervous system abnormalities, including the loss of deep tendon reflexes in the legs, have been known to accompany diabetes mellitus. Symptomatic diabetic neuropathy still remains vaguely defined and the present-day knowledge of its nature is limited. The clinical symptoms are primarily sensory complaints that are occasionally accompanied by pareses, muscular wasting, and autonomic symptoms. The marked morphologic changes found in the nervous system of diabetic patients are more extensive than the clinical findings would suggest.\" The quantification of the clinical findings in diabetic patients with the palesthesiometer demonstrated a rise in the vibration perception threshold and a prolonged preservation of nerve function during ischemia. Soon after the introduction of techniques for measuring nerve conduction velocity in man, Mulder et al. and Gilliatt et al. demonstrated that the conduction velocity of peripheral nerves was decreased in diabetic patients.Gregersen showed that a slight reduction in velocity is present from the beginning of the disease and is followed by a gradual deterioration. He also found that nerve conduction velocity is dependent on the degree of metabolic control. Although the natural history of diabetic neuropathy, defined as the loss of tendon reflexes or as signs and symptoms of monoand polyneuropathy, has recently been extensively described by Pirart,\" only a little additional information concerning the biologic nature of this disease has been published recently. Since the work of Thomas and Lascelles (1965), the Schwann cell has been regarded as the principal site of the peripheral neuropathy of diabetics.' However, during the last ten years, an increasing amount of evidence makes it

The Axonopathy of Diabetic Neuropathy

Edema occurs in peripheral nerves when excessive fluid accumulates either in the interstitium or within the myelin sheath, creating a disturbance in the endoneurial microenvironment. Nerve edema is concomitant with many peripheral neuropathies and can alter the endoneurial microenvironment by increasing pressure, reducing blood flow, or altering electrolyte concentrations in the endoneurial fluid (EF). Not only is it a complication of several diseases of peripheral nerve, but it can independently injure the nerve fiber. This is due to the vulnerability of the vasa nervorum to internal and external pressure. These vessels are characterized by numerous anastomoses that form the epineural and perineurial vascular plexuses (Figs. 1 and 2). Since they pierce the perineurium, pressure at this point causes ischemia, damaging nerve fibers. This chapter reviews new findings concerning the physiology of the endoneurial environment, mechanisms of increased endoneural fluid pressure (EFP), and their pathologic complications.

The Blood-Nerve Barrier and the Pathologic Significance of Nerve Edema

143 endoneural fluid pressure in peripheral nerves of streptozotocin-diabetic and sucrose-intoxicated rats

Microgravimetry of nerve edema

Endoneurial fluid pressure (efp) and pathologic findings in galactose neuropathy: 104

The sorbitol pathway has been suggested as a biochemical mechanism for peripheral neuropathy in diabetes, due to accumulation of osmotically active polyols which cause endoneurial edema. The purpose of this study was to compare endoneurial fluid pressure (EFP) in the peripheral nerves of rats in three experimental models: streptozotocin diabetes, galactose neuropathy, and sucrose intoxication. Endoneurial fluid pressure was measured in 27 diabetic rats at intervals of 4 to 51 weeks after inoculation with streptozotocin and in ten control rats. Elevated fluid pressure was observed in only two diabetic animals, and there was no significant difference in mean EFP between test animals and controls. By contrast, elevated EFP was found in 9 of 11 rats who received a 68% sucrose diet for 48-51 weeks. The mean EFP in these animals was approximately twice normal, and sucrose intoxication thus appears to be a more effective model than streptozotocin diabetes for nerve edema associated with the sorbitol pathway.

Endoneurial Fluid Pressure in Experimental Models of Diabetic Neuropathy

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