Calcitonin gene-related peptide and other neuropeptides in the plasma of patients with soft tissue injury

doi:10.1016/S0024-3205(99)00374-4

Life Sciences

Volume 65, Issue 13, 20 August 1999, Pages 1351-1358

https://doi.org/10.1016/S0024-3205(99)00374-4 Get rights and content

Abstract

Calcitonin gene-related peptide [CGRP] — a powerful vasodilator, is a 37 amino acid peptide that is find primarily in the central and peripheral nervous system. It affects the regulation of local blood flow, smooth muscle tone and glandular secretion. It is an endocrine regulator and in the lungs it also exerts a bronchoconstricting effect. CGRP has a proliferative effect on human endothelial cells. Therefore, it is important for the formation of new vessels, example, in ischemia, inflammations, and in the healing of wounds. Plasma levels of CGRP are increase in patients with chronic cardiac failure and sepsis, indicating that CGRP may be another important peptide in chronic illness. We have therefore measured the release of this peptide and another sensory peptide [Substance P (SP)]; a vasoconstrictor peptide [Endothelin (ET)]; and a perivascular peptide [Neuropeptide Y (NPY)], within 24 hours of injury, in the plasma of patients with soft tissue injury. Neuropeptides were measure by enzyme immunoassay technique. Median:(lowerquartile-upperquartile) in pmol/L CGRP level was elevated in patients [50.37 : (12.4–110.9)] compared to controls [13.9 : (10.9–36.96)] p < 0.05; Endothelin and NPY did not vary much between groups p = NS; ET: patients [8.7 : (1.7–87.1), controls 8.8 : (1.7–32.9)]; NPY: Patients [11.7 : (10.5–14.99), controls 11 : (10.3–12.8)]. SP was increase in patients [302.3 : (79.9–707.3)], than controls [5.6 : (3.2–36.6)] p < 0.05. Furthermore, Elastase (a decisive marker for inflammation and infectious complications), was measure (ng/L), and found to be slightly higher in patients (102:25.5–223), than controls (91.8:45.9–127). In summary, plasma levels of sensory peptides increased significantly, in patients with soft tissue injury, in contrast to vasocostrictor peptides that remained unchanged. These sensory peptides may yet be another group of neuromodulators playing a significant role in immune, pain, inflammatory and wound healing in soft tissue injury patients.

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Substance P acts as an injury messenger in various peripheral tissues (Hong et al., 2009). Systemic substance P levels are elevated in the presence of a tissue injury (Onuoha and Alpar, 1999; 2001) and are also likely to be transiently elevated during endometriosis surgery. Through its binding to NK1R, substance P can exert a broad range of effects, including increased production of inflammatory cytokines (Ho et al., 1996) and chemotaxis of immune cells (Carolan and Casale, 1993; Frode-Saleh et al., 1999).
Can preoperative or perioperative intervention reduce the risk of recurrence of endometriosis caused by either incomplete excision or spillage and dissemination?
A mouse model of endometriosis recurrence caused by spillage and dissemination was first established using 24 female Balb/c mice. The spillage and dissemination model was used to test the efficacy of preoperative use of ketorolac, perioperative use of aprepitant and combined use of propranolol and andrographolide in a prospective, randomized mouse experiment involving 75 mice. The efficacy of these preoperative and perioperative interventions in a mouse recurrence model caused by incomplete excision was also tested using 72 mice. In all experiments, the baseline body weight and hotplate latency of all mice were measured and recorded before the induction of endometriosis, before the primary surgery and before sacrifice. In addition, all lesions were excised, weighed and processed for quantification and immunohistochemistry analysis of E-cadherin, α-SMA, VEGF, ADRB2 and putative markers of recurrence PR-B, p-p65, as well as Masson trichrome staining.
All interventions substantially and significantly suppressed the outgrowth of endometriotic lesions and reduced the risk of recurrence caused by either spillage and dissemination or incomplete excision (P = 0.0007 to 0.042). These interventions also significantly attenuated the generalized hyperalgesia, inhibited the staining of α-SMA, p-p65, VEGF and ADRB2 but increased staining of E-cadherin and PR-B, resulting in reduced fibrosis.
Given the excellent safety profiles of these drugs, these data strongly suggest that preoperative and perioperative intervention may potentially reduce the risk of endometriosis recurrence effectively.
Randomized controlled trial comparison of analgesic drugs for control of pain associated with induced lameness in lactating dairy cattle
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As such, this indicates that analgesic drug treatment caused a reduction in stress levels in the face of mild lameness. Substance P is a neuropeptide that acts as a neurotransmitter (Onuoha and Alpar, 1999; Carrasco and Van de Kar, 2003) that is often used as a pain biomarker (DeVane, 2001; Onuoha and Alpar, 2001; Shen et al., 2006). In evaluation of substance P as an indicator of pain relief, no distinguishing characteristics were seen, which is consistent with previous work by our group (Kleinhenz et al., 2019).
Both the economic loss and welfare implications of lameness affect the dairy industry. Currently no analgesic drugs are approved to alleviate lameness-associated pain in lactating dairy cattle in the United States. In this randomized controlled trial, 48 lactating Holsteins were enrolled to evaluate the effect of oral meloxicam and i.v. flunixin meglumine on induced lameness. Cows were allocated to 1 of 4 treatment groups (n = 12 per group): lameness and flunixin meglumine (LAME + FLU); lameness and meloxicam (LAME + MEL); lameness and placebo (LAME + PLBO); or sham induction and placebo (SHAM + PLBO). Six hours before treatment, arthritis-synovitis was induced in the distal interphalangeal joint with 20 mg of amphotericin B, whereas SHAM cows were given an intra-articular injection of an equal volume (4 mL) of isotonic saline. Cows in LAME + FLU received 2.2 mg/kg flunixin meglumine i.v. and whey protein placebo orally; LAME + MEL were administered 1 mg/kg meloxicam orally and 2 mL/45 kg sterile saline placebo i.v.; LAME + PLBO were administered 2 mL/45 kg sterile saline placebo i.v. and whey protein placebo orally; and SHAM + PLBO received 2 mL/45 kg sterile saline placebo i.v. and whey protein placebo orally. The initial treatment of MEL, FLU, or PLBO was identified as time 0 h and followed by a second dose 24 h later with data collection for 120 h. The methods used to assess analgesic efficacy were electronic pressure mat, visual lameness assessment, visual analog score, plasma cortisol concentration, plasma substance P concentration, mechanical nociception threshold, and infrared thermography imaging. Linear mixed effect modeling was the primary method of statistical analysis. Visual lameness scoring indicated a lower proportion of the FLU + LAME group was lame at the T2 h and T8 h time points in comparison to the positive controls, whereas MEL therapy resulted in a lower proportion of lame cows at the T8 h time point. Cortisol area under the effect curve was lower following FLU therapy compared with LAME + PBLO for the 0–2 h (LSM difference = 35.1 ng·h/mL, 95% CI: 6.8, 63.3 ng·h/mL), 2–8 h (LSM difference = 120.6 ng·h/mL, 95% CI: 77.2, 164.0 ng·h/mL), and 0–24 h (LSM difference = 226.0 ng·h/mL, 95% CI: 103.3, 348.8 ng·h/mL) time intervals. Following MEL therapy, cortisol area under the effect curve was lower than LAME + PLBO for both the 2 to 8 h (LSM difference = 93.6 ng·h/mL, 95% CI: 50.2, 137.0 ng·h/mL) and 0 to 24 h time intervals (LSM difference = 187.6 ng·h/mL, 95% CI: 64.9, 310.4 ng·h/mL). Analysis of data from other assessment modalities failed to discern biologically relevant differences between treatment groups. We conclude that meaningful differences were evident for visual lameness assessment and cortisol from MEL and FLU treatment versus the positive control. Further clinical research is needed toward development of a model that will create reproducible events that are more pronounced in severity and duration of lameness which can be validated as a substitute for naturally occurring lameness cases.
Adenomyosis in mice resulting from mechanically or thermally induced endometrial–myometrial interface disruption and its possible prevention
2020, Reproductive BioMedicine Online
Citation Excerpt :
Among these, the most abundant may be transforming growth factor-β1 (TGF-β1), which has been shown to induce EMT in endometriotic epithelial cells (Zhang et al., 2016). In addition, tissue injury also results in the release of substance P (Onuoha and Alpar, 1999; Onuoha et al., 2001), which may also induce EMT in endometrial epithelial cells (Yan et al., 2019). As a result of this EMT, these epithelial cells, previously immobile within the endometrium, become mobile and invasive, and can move across the disrupted EMI, infiltrate the myometrium and establish the initial adenomyotic foci.
Do uterine procedures potentially disrupting the endometrial–myometrial interface (EMI) induce adenomyosis?
Six prospective, randomized controlled experiments were conducted involving a total of 106 female BALB/c and 12 female C57BL/6 mice. The incidence of adenomyosis was evaluated in these two strains of mouse after mechanically induced EMI disruption (EMID), or thermally induced EMID using electrocoagulation of different intensities. Finally, the incidence was evaluated in mice that had received perioperative administration of aprepitant (an NK1R inhibitor), propranolol (a beta-blocker) or vehicle. Body weight, hot plate latency and grade of myometrial infiltration were evaluated. Histology, immunohistochemistry and histochemistry analyses were also performed.
Mechanical injury to the EMI caused EMID. Adenomyosis developed in the majority of mice in the EMID groups 3 months after mechanically induced EMID but did not develop in the control group (83.3% in C57BL/6 mice, P = 0.015; 100% in BALB/c mice, P = 0.0002). With thermally induced EMID, adenomyosis was found in 30% of the EMID mice 10 weeks later, but the incidence increased to 66.7% if the extent of EMID damage was increased. In mice with perioperative administration of aprepitant or propranolol, the incidence of adenomyosis was reduced from 100% to 58.3% (both P = 0.00034).
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2018, Livestock Science
The aim of this study was to determine the effects of castration and a lidocaine-plus-flunixin (LF) treatment on growth and indicators of pain, inflammation, and liver function in Korean cattle bull calves. Forty Korean cattle bull calves (body weight 197.0 ± 2.94 kg and age 6.3 ± 0.09 months) were each assigned to one of four treatments (n = 10 heads/group): no castration with no LF injection (NC-NLF); no castration with LF injection (NC-LF); castration with no LF injection (C-NLF); and castration with LF injection (C-LF). LF treatment included a local anesthetic lidocaine hydrochloride injection (12 mL of 2% in the scrotum) and intravenous injection of a non-steroidal anti-inflammatory drug, flunixin meglumine (2 mg/kg body weight of 50 mg/mL solution), immediately prior to castration. For the NLF groups, a 0.9% NaCl placebo solution was used. Castration was performed surgically using a Newberry knife and a Henderson castrating tool. Blood was collected immediately before castration and at h 0.5, h 6, d 1, d 3, d 7, and d 14 after castration. Feed intake was recorded daily, and body weight was measured on the day prior to the experiment and at d 14 after castration. Castration tended (P = 0.07) to decrease average daily weight gain, but LF treatment did not affect weight gain. Castration increased both circulating cortisol concentrations (P < 0.001) at h 0.5 after castration and substance P (SP) concentrations (P = 0.001) at h 6 after castration. However, the LF treatment did not significantly reduce cortisol and SP concentrations in castrated animals. Castration increased (P < 0.001) circulating haptoglobin (Hp) concentrations on d 1 and d 3 after castration, and LF treatment tended (P = 0.09) to decrease Hp concentrations on d 1 and decreased (P = 0.02) Hp concentrations on d 3. Castration did not affect glutamic oxaloacetic transaminase (GOT) and glutamic pyruvate transaminase (GPT) concentrations. LF treatment increased GOT concentrations at h 6 (P < 0.001), d 1 (P < 0.001), and d 3 (P = 0.003). LF treatment also increased GPT concentrations on d 1 (P = 0.006) and d 3 (P = 0.003). In conclusion, castration of bull calves resulted in time-sequential increases in circulating concentrations of cortisol at h 0.5, SP at h 6, and Hp on d 1. LF treatment did not significantly reduce elevated cortisol and SP, but tended to decrease elevated Hp concentrations in castrated animals. Our study demonstrates that LF treatment is not sufficient for the reduction of the indicators of pain and inflammation in castrated calves, suggesting that additional alleviation methods are required.
Immunohistochemical analysis of neuropeptides (protein gene product 9.5, substance P and calcitonin gene-related peptide) in hypertrophic burn scar with pain and itching
2014, Burns
Citation Excerpt :
CGRP and SP are both found in unmyelinated sensory nerves fibers of mammalian skin and may mediate this trophic action. The ability of SP and CGRP to stimulate the proliferation of endothelial cells, arterial smooth muscle cells and skin fibroblasts play a role in the angiogenesis of healing tissues [5–7]. Neuropeptides have been recently reported as having an important role in wound repair, and relief from pain and itching sensation.
Neuropeptides have been recently reported as having an important role in wound repair, and relief from pain and itching sensation. The aim of this study was to evaluate the effect of neuropeptides on the wound healing process in hypertrophic scar formation that accompanies severe pain and itching sensation.
We collected forty-three hypertrophic scar specimens from hypertrophic scar release and skin graft under general anesthesia. Immunohistochemical stains for protein gene product (PGP) 9.5, substance P (SP), and calcitonin gene-related peptide (CGRP) were performed. Pain and itching over the scar were recorded using verbal numerical rating scale (VNRS).
In the epidermis, PGP 9.5, SP, and CGRP were significantly increased in hypertrophic scars compared with matched unburned skin. In the reticular dermis, SP and CGRP were significantly increased in hypertrophic scars compared with control. The pain and itching verbal numerical rating scale in scar group were significantly higher compared to control. In the papillary dermis, the PGP represented significant correlation with Itching P (correlation coefficient 0.698) and the SP represented significant correlation with pain N (correlation coefficient −0.671). In the reticular dermis, the SP represented significant correlation with pain N (correlation coefficient −0.614) and CGRP represented significant correlation with pain P/Itching P (correlation coefficient 0.801/0.611).
Neuropeptides such as PGP 9.5, SP, and CGRP seem to affect scarring via sensory neurotransmission, it have a regulatory role for pain and itching sensation in hypertrophic scars.
Assessment and Management of Pain Associated with Castration in Cattle
2013, Veterinary Clinics of North America - Food Animal Practice

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Calcitonin gene-related peptide and other neuropeptides in the plasma of patients with soft tissue injury

Abstract

Gastroenterology

Neuropeptide

Lancet

Trends. Neurosci.

Life. Sci.

Brain. Research.

Adv. Immunol.

Biochem. Biophysiol. Res. Commun.

Nature

Neuropeptide

Cardiology

Nature

Crit. Care. Med.

Shock