Spatial Distribution of Nociceptive Neuropeptide and Nerve Growth Factor Depletion in Experimental Diabetic Peripheral Nervous System

Kanbayashi, Hiroshi; Itoh, Hiroshi; Kashiwaya, Tagui; Atoh, Keita; Makino, Isao

doi:10.1177/147323000203000507

Cited by 11 publications

(9 citation statements)

References 36 publications

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“…Kanbayashi et al investigated the spatial distribution of nociceptive neuropeptide SP in diabetic rats. Their results indicated that SP and nerve growth factor (NGF) levels decreased at lumbar dorsal root ganglion (DRG) early in diabetes but at later times their reduction occurred in both the lumbar and cervical DRG which is consistent with the aforementioned clinical observation 78 . After activation of Aδ and C fibers via nociceptive stimulation in peripheral tissues, nociceptive neuropeptide SP is produced in peptidergic DRG neurons to mediate nociception.…”

Section: Dysregulated Sp Expression In Diabetes‐associated Neuropathysupporting

confidence: 65%

The neuropeptide substance P/neurokinin‐1 receptor system and diabetes: From mechanism to therapy

et al. 2023

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Diabetes is a significant public health issue known as the world's fastestgrowing disease condition. It is characterized by persistent hyperglycemia and subsequent chronic complications leading to organ dysfunction and, ultimately, the failure of target organs. Substance P (SP) is an undecapeptide that belongs to the family of tachykinin (TK) peptides. The SP-mediated activation of the neurokinin 1 receptor (NK1R) regulates many pathophysiological processes in the body. There is also a relation between the SP/NK1R system and diabetic processes. Importantly, deregulated expression of SP has been reported in diabetes and diabetes-associated chronic complications. SP can induce both diabetogenic and antidiabetogenic effects and thus affect the pathology of diabetes destructively or protectively. Here, we review the current knowledge of the functional relevance of the SP/NK1R system in diabetes pathogenesis and its exploitation for diabetes therapy. A comprehensive understanding of the role of the SP/NK1R system in diabetes is expected to shed further light on developing new therapeutic possibilities for diabetes and its associated chronic conditions.

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Section: Dysregulated Sp Expression In Diabetes‐associated Neuropathysupporting

confidence: 65%

The neuropeptide substance P/neurokinin‐1 receptor system and diabetes: From mechanism to therapy

et al. 2023

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“…Recently, we have demonstrated that >80% of sensory neuron MOR colocalize with trkA in the NGF-dependent subpopulation of small DRG neurons (11). In diabetic rats, peripheral sensory neurons suffer from a persistent deficit in NGF concentration (24,44,45). Moreover, growth factor deprivation leads to the upregulation of Rab7 expression (23).…”

Section: Discussionmentioning

confidence: 99%

Rab7 Silencing Prevents μ-Opioid Receptor Lysosomal Targeting and Rescues Opioid Responsiveness to Strengthen Diabetic Neuropathic Pain Therapy

et al. 2013

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Painful diabetic neuropathy is poorly controlled by analgesics and requires high doses of opioids, triggering side effects and reducing patient quality of life. This study investigated whether enhanced Rab7-mediated lysosomal targeting of peripheral sensory neuron μ-opioid receptors (MORs) is responsible for diminished opioid responsiveness in rats with streptozotocin-induced diabetes. In diabetic animals, significantly impaired peripheral opioid analgesia was associated with a loss in sensory neuron MOR and a reduction in functional MOR G-protein-coupling. In control animals, MORs were retained mainly on the neuronal cell membrane. In contrast, in diabetic rats, they were colocalized with upregulated Rab7 in LampI-positive perinuclear lysosome compartments. Silencing endogenous Rab7 with intrathecal Rab7-siRNA or, indirectly, by reversing nerve growth factor deprivation in peripheral sensory neurons not only prevented MOR targeting to lysosomes, restoring their plasma membrane density, but also rescued opioid responsiveness toward better pain relief. These findings elucidate in vivo the mechanisms by which enhanced Rab7 lysosomal targeting of MORs leads to a loss in opioid antinociception in diabetic neuropathic pain. This is in contrast to peripheral sensory neuron MOR upregulation and antinociception in inflammatory pain, and provides intriguing evidence that regulation of opioid responsiveness varies as a function of pain pathogenesis.

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“…Changes in expression of substance P may also affect C-fiber nociceptive function. In STZ-diabetic rats, reduced substance P levels have been reported in dorsal root ganglia [14, 40] and both the peripheral [27, 40] and central [2] projections of primary afferents. Reductions in substance P reflect reduced synthesis of this neuropeptide and consequent decreases in the amount undergoing axonal transport [34] and released in the spinal cord after peripheral noxious stimulation [2].…”

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confidence: 99%

Dissociation of thermal hypoalgesia and epidermal denervation in streptozotocin-diabetic mice

Beiswenger

Calcutt

Mizisin

2008

Neuroscience Letters

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The quantification of epidermal innervation, which consists primarily of heat-sensitive C-fibers, is emerging as a tool for diagnosing and staging diabetic neuropathy. However, the relationship between changes in heat sensitivity and changes in epidermal innervation has not yet been adequately explored. Therefore, we assessed epidermal nerve fiber density and thermal withdrawal latency in the hind paw of Swiss Webster mice after two and four weeks of streptozotocin-induced diabetes. Thermal hypoalgesia developed after only two weeks of diabetes, but a measurable reduction in PGP9.5-immunoreactive epidermal nerve fiber density did not appear until four weeks. These data suggest that impaired epidermal nociceptor function contributes to early diabetes-induced thermal hypoalgesia prior to the loss of peripheral terminals.Keywords diabetic neuropathy; epidermal nerve fiber density; GAP-43; PGP9.5; substance P; thermal hypoalgesia Nearly half of all diabetic patients will develop some form of peripheral neuropathy, with distal symmetric polyneuropathy the most common form [24,33]. Depletion of intra-epidermal nerve fibers (IENFs), representing the peripheral terminals of nociceptive unmyelinated C-fibers, appears to be an early index of diabetic neuropathy [30]. Resulting sensory disorders in diabetic patients range from hyperalgesia and allodynia to progressive hypoalgesia that, in conjunction with microvascular disease and impaired wound healing, leaves limbs vulnerable to infections and amputation.Diabetes-induced reductions in epidermal innervation have been observed in multiple clinical studies, as well as in diabetic primates and rodents [for review see 1,17 and references therein]. IENF loss has been correlated with measures of nerve function to assess its predictive value for other aspects of diabetic neuropathy. In humans, reductions in IENF density have been correlated with changes in pressure and vibration perception, total neurological disability score and neuropathy status [25,31]. In rats, IENF loss correlates with changes in caudal sensory nerve conduction velocity [16].One would logically predict that loss of thermal sensation is a consequence of diminished epidermal innervation. Indeed, reductions in IENF density induced by topical application of Correspondence to: Andrew P. Mizisin, Ph.D., Department of Pathology 0612, School of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla CA 92093-0612, Tel: (858) 822-3894, FAX: (858) 534-1886, email: amizisin@ucsd.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. capsaicin to the skin ...

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Spatial Distribution of Nociceptive Neuropeptide and Nerve Growth Factor Depletion in Experimental Diabetic Peripheral Nervous System

Cited by 11 publications

References 36 publications

The neuropeptide substance P/neurokinin‐1 receptor system and diabetes: From mechanism to therapy

The neuropeptide substance P/neurokinin‐1 receptor system and diabetes: From mechanism to therapy

Rab7 Silencing Prevents μ-Opioid Receptor Lysosomal Targeting and Rescues Opioid Responsiveness to Strengthen Diabetic Neuropathic Pain Therapy

Dissociation of thermal hypoalgesia and epidermal denervation in streptozotocin-diabetic mice

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