Highlights Pig peripheral neuritis trauma model mimics cutaneous human pathologies. Pig skin anatomically similar to humans, unlike rodent. Pig PNT model provides better data than rodent for translational pain research.
CB 2 cannabinoid receptors (CB 2 ) are a promising therapeutic target that lacks unwanted side effects of CB 1 activation. However, the cell types expressing CB 2 that mediate these effects remain poorly understood. We used transgenic mice with CB 2 promoter-driven expression of enhanced green fluorescent protein (EGFP) to study cell types that express CB 2 and suppress neuropathic nociception in a mouse model of chemotherapy-induced peripheral neuropathy. Structurally distinct CB 2 agonists (AM1710 and LY2828360) suppressed paclitaxel-induced mechanical and cold allodynia in CB 2 EGFP reporter mice with established neuropathy. Antiallodynic effects of AM1710 were blocked by SR144528, a CB 2 antagonist with limited CNS penetration. Intraplantar AM1710 administration suppressed paclitaxel-induced neuropathic nociception in CB 2 EGFP but not CB 2 knockout mice, consistent with a local site of antiallodynic action. mRNA expression levels of the anti-inflammatory cytokine interleukin-10 were elevated in the lumbar spinal cord after intraplantar AM1710 injection along with the proinflammatory cytokine tumor necrosis factor alpha and chemokine monocyte chemoattractant protein-1. CB 2 EGFP , but not wildtype mice, exhibited anti-GFP immunoreactivity in the spleen. However, the anti-GFP signal was below the threshold for detection in the spinal cord and brain of either vehicle-treated or paclitaxel-treated CB 2 EGFP mice. EGFP fluorescence was coexpressed with CB 2 immunolabeling in stratified patterns among epidermal keratinocytes. EGFP fluorescence was also expressed in dendritic cells in the dermis, Langerhans cells in the epidermis, and Merkel cells. Quantification of the EGFP signal revealed that Langerhans cells were dynamically increased in the epidermis after paclitaxel treatment. Our studies implicate CB 2 expressed in previously unrecognized populations of skin cells as a potential target for suppressing chemotherapy-induced neuropathic nociception.
In addition to large plexiform neurofibromas (pNF), NF1 patients are frequently disfigured by cutaneous neurofibromas (cNF) and are often afflicted with chronic pain and itch even from seemingly normal skin areas. Both pNFs and cNF consist primarily of benign hyperproliferating nonmyelinating Schwann cells (nSC). While pNF clearly arise within deep nerves and plexuses, the role of cutaneous innervation in the origin of cNF and in chronic itch and pain is unknown. First, we conducted a comprehensive, multi-molecular, immunofluorescence (IF) analyses on 3mm punch biopsies from three separate locations in normal appearing, cNF-free skin in 19 NF1 patients and skin of 16 normal subjects. At least one biopsy in 17 NF1 patients had previously undescribed micro-lesions consisting of a small, dense cluster of nonpeptidergic C-fiber endings and the affiliated nSC consistently adjoining adnexal structures—dermal papillae, hair follicles, sweat glands, sweat ducts, and arterioles—where C-fiber endings normally terminate. Similar micro-lesions were detected in hind paw skin of mice with conditionally-induced SC Nf1 -/- mutations. Hypothesizing that these microlesions were pre-cNF origins of cNF, we subsequently analyzed numerous overt, small cNF (s-cNF, 3–6 mm) and discovered that each had an adnexal structure at the epicenter of vastly increased nonpeptidergic C-fiber terminals, accompanied by excessive nSC. The IF and functional genomics assays indicated that neurturin (NTRN) and artemin (ARTN) signaling through cRET kinase and GFRα2 and GFRα3 co-receptors on the aberrant C-fiber endings and nSC may mutually promote the onset of pre-cNF and their evolution to s-cNF. Moreover, TrpA1 and TrpV1 receptors may, respectively, mediate symptoms of chronic itch and pain. These newly discovered molecular characteristics might be targeted to suppress the development of cNF and to treat chronic itch and pain symptoms in NF1 patients.
This study investigated quantifiable measures of cutaneous innervation and algesic keratinocyte biomarkers to determine correlations with clinical measures of patient pain perception, with the intent to better discriminate between diabetic patients with painful diabetic peripheral neuropathy (PDPN) compared to patients with low-pain diabetic peripheral neuropathy (lpDPN) or healthy control subjects. A secondary objective was to determine if topical treatment with a 5% lidocaine patch resulted in correlative changes among the quantifiable biomarkers and clinical measures of pain perception, indicative of potential PDPN pain relief. This open-label proof-of-principle clinical research study consisted of a pre-treatment skin biopsy, a 4-week topical 5% lidocaine patch treatment regimen for all patients and controls, and a post-treatment skin biopsy. Clinical measures of pain and functional interference were used to monitor patient symptoms and response for correlation with quantitative skin biopsy biomarkers of innervation (PGP9.5 and CGRP), and epidermal keratinocyte biomarkers (Nav1.6, Nav1.7, CGRP). Importantly, comparable significant losses of epidermal neural innervation (intraepidermal nerve fibers; IENF) and dermal innervation were observed among PDPN and lpDPN patients compared with control subjects, indicating that innervation loss alone may not be the driver of pain in diabetic neuropathy. In pre-treatment biopsies, keratinocyte Nav1.6, Nav1.7, and CGRP immunolabeling were all significantly increased among PDPN patients compared with control subjects. Importantly, no keratinocyte biomarkers were significantly increased among the lpDPN group compared with control. In post-treatment biopsies, the keratinocyte Nav1.6, Nav1.7, and CGRP immunolabeling intensities were no longer different between control, lpDPN, or PDPN cohorts, indicating that lidocaine treatment modified the PDPN-related keratinocyte increases. Analysis of the PDPN responder population demonstrated that increased pretreatment keratinocyte biomarker immunolabeling for Nav1.6, Nav1.7, and CGRP correlated with positive outcomes to topical lidocaine treatment. Epidermal keratinocytes modulate the signaling of IENF, and several analgesic and algesic signaling systems have been identified. These results further implicate epidermal signaling mechanisms as modulators of neuropathic pain conditions, highlight a novel potential mode of action for topical treatments, and demonstrate the utility of comprehensive skin biopsy evaluation to identify novel biomarkers in clinical pain studies.
Vasculopathy complications of T2D cause limited tissue perfusion, ulcers, and often amputation. Mechanisms underlying T2D vasculopathy remain ambiguous. Compare to normal controls, multi-molecular immunofluorescence of glabrous hand and foot skin biopsies from 12T2D monkeys and 35 humans revealed a consistent depletion of CGRP containing sensory innervation (CGRPsens) that normally mediates local vasodilatation of cutaneous resistance arterioles. By contrast, arteriole vasoconstricting noradrenergic sympathetic innervation (NAsymp) remained largely intact. Thus, a vasoconstrictive imbalance could potentially impede arteriole blood flow contributing to hypertension and reduced capillary perfusion. Further analyses of monkeys indicated that this neurovascular pathology may begin during prediabetic metabolic syndrome. Surprisingly, the NAsymp and a separate set of CGRPsens to precapillary arterioles and capillaries initially remained intact in the T2D monkeys and humans and may even be increasing. This may be a maladaptive response to dilate and increase capillary perfusion to compensate for a reduced arteriole supply. As such, dilatation of the capillaries may increase their blood volume, but inadvertently reduce the rate of blood flow resulting in anoxia. In advanced T2D, a de novo superficial shunt pathology appears and capillaries begin to deteriorate. In contrast to this neurovascular pathology occurring early or before overt T2D onset, we and others have non-painful and painful T2D neuropathies involving other types of tactile sensory innervation typically occur after T2D hyperglycemia is well established. Thus, the early stage neurovascular pathology may be a direct contributor to the onset of 2TD instead of being a consequence of TD2 hyperglycemia, and may be a potential target for early detection and pre-emptive treatment. Disclosure F. Rice: None. G. Houk: None. B.C. Hansen: None. X. Tigno: None. P. Albrecht: None.
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