Combined Acetaminophen and L-carnosine Treatment Prevented Anxiety-like Behaviour in Chronic Constriction Injury-induced Peripheral Neuropathy

doi:10.21203/rs.3.rs-2104880/v1

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Combined Acetaminophen and L-carnosine Treatment Prevented Anxiety-like Behaviour in Chronic Constriction Injury-induced Peripheral Neuropathy

https://doi.org/10.21203/rs.3.rs-2104880/v1

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Background

Emotional derangement contributes to the worsening quality of life in a patient suffering from neuropathic pain (NP). Here, we report the therapeutic beneficial effects of combined acetaminophen and L-carnosine treatment in chronic constriction injury (CCI)-induced NP and associated comorbidities in male Wistar rats.

Methods

Seven experimental groups of male wistar rats were treated with normal saline, acetaminophen or acetaminophen and L-carnosine. Tail-immersion, Elevated Zero-maze, and light/dark box were used to assess pain and anxiety-like behaviours in rats. The kidney and liver were subjected to histotoxicological assessment after twenty-one days of treatments.

Results

Thermal hyperalgesia as well as pronounced anxiety-like behaviours were evident in CCI-induced rats. Ligated Wistar showed a significant (p < 0.001) increase in time spent in the close arms and decreased time duration in open arms compared with the unligated control in zero-maze. There was a significant decrease (p > 0.05) in time duration in the lightened compartment and an increase in time duration in the dark compartment of the light and dark box in ligated rats compared with unligated rats. Treatment with acetaminophen or its combination with L-carnosine improved the anxiolytic-like comorbid and pain behaviours in ligated rats. Combined acetaminophen and L-carnosine therapy prevented hepato-and-nephrotoxicity that is characterized in rats treated with acetaminophen alone.

Conclusion

Hence, combined acetaminophen and L-carnosine treatment is a potential treatment for CCI pain and its comorbidities.

Neuropathic pain

anxiety

L-carnosine

Acetaminophen

Nephrotoxicity

Hepatotoxicity

comorbidity

Impairment to the somatosensory neurons in terms of a lesion, traumatic injury and disease results in derangement of neurotransmission that lead to neuropathic pain (NP). Patient with NP is characterized by hyperalgesia, excessive perception of painful stimuli, and allodynia, painful perception of innocuous stimuli. Mood alterations (such as depression), neurocognitive changes, and anxiety are comorbid that are usually associated with neuropathic pain [1–4]. Comorbid depressive symptoms (CDS) and anxiety disorder in chronic pain are common health problems and tend to contribute to excessive duration and intensity of pain [5, 6]. The neurobiological mechanism of these disorders and pain is still unclear. It has been opinioned that comorbid conditions heighten pain intensity, and in turn, neuropathic pain aggravates the comorbid conditions. The interrelationship of these factors is complex, as these comorbidities are associated with themselves leading to the imbalance in a patient's quality of life [2]. The association of neuropathic pain with depression and anxiety is highly prevalent in the health system.

These comorbidities might also negatively impact response to analgesics [7]. Currently, anticonvulsants (such as pregabalin and gabapentin) [8] and antidepressants (such as Duloxetine and venlafaxine) [9] are common therapeutic agents used in the management of NP. An important factor influencing outcomes is the presence of comorbidities [1, 3, 4, 10]. Comorbid of NP, depression and anxiety, must be fully considered in the search for a suitable treatment if the patient is to be restored to optimal functionality and improved quality of life.

Carnosine is a protein-building block that is naturally produced in the body by the liver from beta-alanine and histidine. It is produced endogenously in the muscles, heart, brain, and many other physiological systems where it aids the well-being of biological activities. L-carnosine is a commercially available synthetic form of carnosine. It has been widely used as a supplement. Its antioxidant activity is mediated by different mechanisms involving metal ion chelation and scavenging reactive oxygen species (ROS) and peroxyl radicals [11]. L-carnosine is rumoured to be used for the neurodegenerative disease but there is no scientific evidence to support these uses.

Acetaminophen (N-Acetyl- para-aminophenol) also known as “paracetamol”, is the active metabolite of acetanilide and phenacetin. It is one of the most widely used analgesics and antipyretics (fever reducer) [12]. The use of acetaminophen for the treatment of NP has continued to generate debates among researchers and care providers. Some studies show that acetaminophen was ineffective or has low efficacy in the treatment of NP [13–15] while there was a contrary opinion stating that acetaminophen improves hyperalgesia and allodynia symptoms of NP [16]. There are great concerns about the hepatoxicity side-effect of acetaminophen. It has been thought to be responsible for most cases of liver failures [17–19]. Acetaminophen intoxication induces excessive production of N-acetyl-p-benzoquinoneimine (NAPQI) which triggers a cascade of cellular events that ultimately result in hepatocellular death [20].

Reports on the anxiety-like effect and emotional disturbance after the administration of acetaminophen have been highly debated. Umathe and his colleagues noted that acetaminophen induces an anxiolytic effect via its metabolites (N-arachidonoylphenolamine (AM404) and anandamide) that acted on cannabinoid receptor-1 (CB1) [21]. However, Chen and his colleagues reported that acetaminophen induces emotional disturbances in healthy rats, but, reduces anxiety and anhedonia at a low dose in neuropathic painful conditions [22].

The use of combined therapies has been the best recommendation for the treatment of NP. We recently showed that combined treatment of CCI-induced NP in rats with acetaminophen and L-carnosine abated thermal and mechanical hyperalgesia [23]. Clear-cut documentation on the anti-comorbid effects of their combined treatment is yet to be reported. Hence this report is focused on the anti-comorbid effects, anti hepatotoxicity and anti-nephrotoxicity effects of coadministration of acetaminophen and L-carnosine treatment in sciatic nerve ligation-induced neuropathic pain in Wistar rats.

Animals

Fifty sixty male Wistar rats weighing 160 g to 180 g, and bred at Ogbomosho Animal House, Oyo State, Nigeria were used for the study. The animals were grouped into seven containing eight randomly selected rats based on estimated sample size using SigmaPlot version 12 software (Systat Software, Inc., Chicago, IL). Animals were housed and acclimatised for seven days in the animal facilities of the Faculty of Basic Medical Sciences, University of Ilorin, Nigeria, under standard conditions with free access to food and water. All experimental protocols were approved by the University of Ilorin Ethical Review Committee.

Chronic Constriction Injury

Chronic constriction injury (CCI) was used to induce peripheral neuropathy in Wistar rats as described in our previous study [23]. In brief, rats were anaesthetized with ketamine hydrochloride (100 mg/kg, intraperitoneal injection [i.p.]). The hairs on the lower back and thigh of the rats were shaved and the surgical area was disinfected with methylated spirit. The skin of the lateral surface of the right thighs was incised, and cuts were made bluntly through the biceps. The sciatic nerves were then exposed and freed from adhering tissues. Four ligatures (silk sutures size 4 − 0) were placed loosely around each sciatic nerve without disrupting the epineural blood supply. After performing the ligation, muscular and skin layers were sutured in layers with catgut and suturing thread respectively. In the sham operations, the same procedure was followed as described above. However, the sciatic nerve in sham rats was left intact without placing ligating suture silk around it. Following this, the rats were allowed to recover in a clean cage and then returned to their respective housing unit with an adequate supply of food and water.

Drug And Treatment Schedule

Pretreated groups were administered either acetaminophen or in combination with L-carnosine for seven consecutive days before the ligation of the sciatic nerve and were followed up with the same dose for the next 21 consecutive days after sciatic nerve ligation. Post-treated groups were administered orally with normal saline, acetaminophen alone or in combination with L-carnosine for 21 consecutive days after sciatic nerve ligation. The summary of the grouping and treatments are as follows:

Group A (Control)

10 ml/Kg/body weight of normal saline

Group B (Sham)

10 ml/Kg/body weight of normal saline

Group C (Ligated control)

10 ml/Kg/body weight of normal saline

Group D (Pre-treated acetaminophen)

200mg/kg/body weight

Group E (Post-treated acetaminophen): 200mg/kg/body weight Group F (Pre-treated co-treatment): acetaminophen (200mg/kg/body weight) + L-carnosine (100mg/kg/body weight)

Group G: (Post-treated co-treatment): acetaminophen (200mg/kg/body weight) + L-carnosine (100mg/kg/body weight)

L-carnosine was a product of Hubei Hongpeptide Biotechnology Co., Ltd. China while acetaminophen was a product of Anhui BBCA Pharmaceutical Co., Ltd. China. The dosage of 100mg/kg/body weight of L-carnosine [24] and 200 mg/kg of acetaminophen [16] was used based on a previous study. Each group were treated one after the other to minimise confounder.

BEHAVIOURAL TESTS

Assessment of pain behaviours to thermal and mechanical stimuli was carried out for animal baseline (before CCI and three days after CCI), and on the 3rd, 7th, 14th, and 21st day of post-ligation treatments. The researchers conducting the behavioural tests were blinded to both the treatment and grouping of the rats throughout the tests.

Thermal hyperalgesia

Thermal hyperalgesia was evaluated with the use of a water bath as described in our previous study [25]. Briefly, a tail immersion test was carried out using a water bath with temperature sets at 55°C ± 0.5°C. The animal was restricted with careful hand grip and the distal part of the tail was immersed in the water bath. The time taken for the rat to flick or withdraw the tail from the water bath was taken as tail withdrawal latency (TWL) and was recorded in milliseconds chronologically with a stopwatch.

Zero-maze Test

Anxiety-like behaviour was investigated using an elevated zero-maze (EZM) apparatus as described by Olajide and his colleague [26]. EZM is made up of plywood of 120 cm in diameter, 10 cm wide path, 31 cm wall height and 60 cm high from the floor. Rats were placed at a boundary between an open and a closed compartment, facing the inside of the closed zone. Each rat was allowed to explore the maze for 5 minutes with an overhead recording camera. The time spent in the open and closed compartments was recorded as well as the number of faecal boli was estimated. EZM test was carried out before and after ligation and on the tenth and twentieth days of administration.

Light and dark Maze (LDM) test

anxiety-like behaviour was further evaluated using the light and dark paradigm [27]. Rats were introduced into the lightbox and allowed to explore the LDM for 5 minutes. Activities of rats in the Light and dark box were recorded with a camera. The total time spent in the lightbox and dark box was estimated from the recording. The frequency of defecation was estimated by counting the number of faecal boli after five minutes duration.

Histological Study

The transverse section of the prefrontal cortex, liver and kidney were assessed using hematoxylin and eosin (H&E) stain, as described in the work of Muthuraman and his colleagues [28]. Briefly, after 21 days of treatment, the rats were euthanized with an intraperitoneal injection of excess ketamine hydrochloride (700µl) and subsequently perfused transcardially with normal saline followed by 10% formaldehyde. The brain, liver and kidney were quickly removed and fixed in 10% formaldehyde for 24 h and followed by 72 hours in sucrose solution. The tissue was blocked with paraffin wax. A section 5 µm thick were made from each tissue and stained in haematoxylin & eosin solution. Histological details of the sections were viewed under the light microscope with a magnification of x100, x200 and ×400 power. A micrograph was taken and analyzed using Amscope software version 3.7.

Statistical Evaluation

All results were expressed as mean ± standard error of the mean (n = 8). Graph Pad prism was used to analyze all data. Two-way analysis of variance (ANOVA) was used to analyze all the behaviour parameters. Bonferroni post hoc multiple comparisons were used to determine the level of significance. The significant level was set at P < 0.05.

Thermal Hyperagesial Test

All the Wistar rats used for this experiment were subjected to thermal nociceptive tests before the induction of NP. This test showed that animals were not in a subjected state of hyperalgesia before the induction of NP. There were no significant differences (p > 0.05) in the thermal perception of the cohort of rats used before surgical induction of NP as indicated in Fig. 1. Subsequently, after the induction of neuropathic pain, thermal hyperalgesia was noted in all the ligated Wistar rats on the seventh day of post-induction. The degree of thermal hypersensitivity was resisted in the group pretreated with acetaminophen which showed a significant (p < 0.05) increase in tail withdrawal latency (TWL) compared with the ligated control group (2.99 ± 0.23 secs Vs 2.12 ± 0.12 secs). Subsequently, all the treatment groups with either acetaminophen or its combination with L-carnosine showed a significant increase (p < 0.05) in TWL compared with the ligated control group. Pretreatment with combined acetaminophen and L-carnosine therapy showed the most effective response against thermal hypersensitivity when compared with the ligated control group on the twenty-first day of the post-ligation thermal hyperalgesia test (3.38 ± 0.24 secs Vs 1.72 ± 0.07 secs). Combine treatment with acetaminophen and L-carnosine shows no significant difference (p > 0.05) from the unligated groups on the twenty-first-day post-induction thermal hyperalgesia test (Fig. 1). TWL was significantly low in the group treated with acetaminophen alone compared with the unligated group on the seventh, fourteenth and twenty-first post-NP induction tests.

Zero Maze Anxiolytic-like Behavioural Test

Anxiolytic-like behaviour was observed in the ligated Wistar rats as indicated in Fig. 2A-C. Ligated Wistar showed a significant (p < 0.001) increase in time spent in the close arms (291.75 ± 0.82 secs Vs 242.05 ± 2.95 secs) and decreased time duration in open arms (1.75 ± 0.16 secs Vs 8.59 ± 0.36 secs) compared with the unligated control (Fig. 2A-B). There was also significant (p < 0.001) increases in the frequency of faecal boli defecation in ligated rats (3.75 ± 0.16 Vs 0.5 ± 0.19) compared with unligated rat (Fig. 3C). Treatment with acetaminophen or its combination L-carnosine improved the anxiolytic-like comorbid behaviour in ligated rats. Reduced anxiety-like behaviour is marked observed in groups pretreated with acetaminophen or its combination L-carnosine than in post-treated groups. Acetaminophen pretreated group showed insignificant differences (p > 0.05) in time duration on the open arm on the twentieth-day post-NP induction test compared with the unligated group (7.77 ± 0.34 secs Vs 8.59 ± 0.36 secs). However, the combined treatment with L-carnosine showed significant increases in open arm duration on the tenth (12.09 ± 0.64 secs Vs 10.25 ± 0.65 secs) and twentieth-day (11.36 ± 0.7 secs Vs 8.59 ± 0.36 secs) post NP induction test compared with an unligated group (Fig. 2A). There was an insignificant difference (p > 0.05) in time spent at the close arm in the group pretreated with combined acetaminophen and L-carnosine therapy compared with unligated control (245.1 ± 1.18 secs Vs 242 ± 2.95 secs) on the twentieth-day post-induction test (Fig. 2B). Treatment with acetaminophen or its combination L-carnosine significantly (p < 0.001) reduces the frequency of faecal boli defecation compared with ligated control (Fig. 2C).

Light and Dark Box Anxiety-like Behavioural test: Anxiety-like behaviours were well evidenced in ligated Wistar rats. There is a significant decrease (p > 0.05) in time duration in the lightened compartment in ligated rats compared with unligated rats (6.88 ± 0.44 secs Vs 29.98 ± 1.90 secs) (Fig. 3A). There are also significant increases (p < 0.001) in the time spent at the close compartment in ligated rats compared with unligated rats (293.10 ± 0.44 secs Vs 255.1 ± 1.80 secs) (Fig. 3B). Treatment with acetaminophen alone or in combination with L-carnosine subsequently after CCI showed increases in time spent in the lightbox and decreased close compartment time duration (Fig. 3A-B). Seven days of pretreatment with acetaminophen alone or its combination with L-carnosine before CCI completely prevent the development of anxiety-like behaviour. Combine pretreatment with acetaminophen and L-carnosine showed a significantly longer time duration in the lightened compartment compared with unligated Wistar rats (10th-day trial: 44.05 ± 1.83 secs Vs 22.52 ± 2.01 secs; 20th-day trial: 25.38 ± 3.17 secs Vs 13.34 ± 1.14 secs) as represented in Fig. 3A-B.

Histological Study

CCI have minimal impact on the morphological structure of the kidney and liver. Minimal retraction of the glomerulus from the bowman capsule was observed (black arrow) as indicated in Fig. 4C. Treatment with acetaminophen alone showed marked structural deficits that indicated high nephrotoxicity. There was wide glomerular retraction (black arrow), disorganized Bowman capsule (red broken arrow) and vacuolation of the glomerulus and renal tubules (black broken arrow) in the rats post-treated with acetaminophen (Fig. 4D). These morphological deficits were severe in the acetaminophen pretreated group (Fig. 4E). Reduced retraction, vacuolation and improved Bowman capsule structure were observed in the combined acetaminophen and L-carnosine post-treatment group (Fig. 4F). The observed kidney morphological structure of the pre-treated rat with co-administration of acetaminophen and L-carnosine was comparable with the unligated rats (Fig. 4G).

Hepatotoxicity was observed in the acetaminophen-treated groups. This is marked by increased vacuolation of the sinusoid (red arrowhead), significantly reduced hepatocytes, and pyknosis (red arrow) (Fig. 5D-E). There was pronounced hepatic dysmorphology in the acetaminophen-pretreated group compared with the post-treated acetaminophen group. Combined post-treatment with acetaminophen and L-carnosine groups showed indifferent hepatic morphology with unligated and ligated control groups. There is a normal appearance of the sinusoid, hepatocyte, Kupfer cells and increased circulating leukocyte in rats pre-treated with co-administration of acetaminophen and L-carnosine as indicated in Fig. 5G.

The allegiance of the index of peripheral neuropathy (NP) with comorbidities has been critical in the maintenance of neuropathic pain. The degree of escalation of mood disorder results in changes in pain intensity due to neuroplasticity occurrence in various pain-associated areas in the central nervous system [10, 29, 30]. This interrelation is complex, it worsens the quality of life of the patients, and might account for the unsuccessful rate of treatment of the NP [3, 4]. This current study demonstrated the potential therapeutic values of combined acetaminophen and L-carnosine treatment of NP and associated comorbid anxiety disorder.

The anti-hyperalgesic and anti-allodynic effects of the combined acetaminophen and L-carnosine treatment have been reported recently [23]. The result from the current study also confirms the anti-hyperalgesic effect of acetaminophen or its combination with L-carnosine. The use of zero-maze and light-and-dark-box for the assessment of anxiety-like behaviour has been widely demonstrated in the literature [31, 32]. Treatment with acetaminophen reversed the developed anxiety-like comorbidity of NP. Similar reports on the anti-anxiolytic properties of acetaminophen were reported in separate studies [21, 22]. However, the safety of the use of acetaminophen has been a major concern. Hepatotoxicity has been a major challenge with the use of acetaminophen. Several studies have associated liver failure with the use of acetaminophen [20, 33]. Our study revealed that treatment with acetaminophen poses a high risk for the development of nephrotoxicity and hepatotoxicity. Increased morphological derangement of the liver tissue, Bowman corpuscle as well as glomerulus is well prominent. The inevitable length of treatment with acetaminophen worsens the degree of both nephro-and-hepatotoxicity in NP.

Interestingly, the use of combined acetaminophen and L-carnosine abated not only the comorbidity of NP but also acetaminophen-mediated hepato-and-nephrotoxicity. Pretreatment with this combined therapy prevents the development of the anxiety disorder comorbidity whereas the post-treatment with the combined therapy reversed the developed anxiety-like behaviour in ligated rats. Although previous researchers pointed out that a low dose of acetaminophen is beneficial for the manifestation of anti-anxiety-like behaviour in NP [22], our results strongly pointed out that the dosage of 200mg/kg of acetaminophen effectively reversed anxiety-like behaviour. This anti-anxiolytic property is best mediated when combined with L-carnosine. Anxiety-like behaviour is voided and prevented with combined acetaminophen and L-carnosine pretreatment. This property of the combined treatment may also contribute to the strong anti-hyperalgesic and anti-allodynic efficacy observed in our previous report [23]. Hence, we concluded that effective NP and its related anxiety disorder treatment can be achieved with either pretreatment or post-treatment with combined acetaminophen and L-carnosine.

Combined acetaminophen and L-carnosine treatment prevented the occurrence of hepato-and-nephrotoxicity. The observed preservation of the structural integrity of the kidney and liver was more pronounced in the pretreatment group than in the post-treatment group. This may be due to variations in the treatment duration which can play a vital role. This probably accounts for the improved structural integrity of the liver and kidney than a combined post-treatment. The absence of derangement in the Bowman’s capsule and glomerular epithelium pointed to the contributory role of the L-carnosine. L-carnosine has been known for its antioxidant activities via ion chelation and scavenging of the reactive oxygen species [11]. We propose that the antioxidant role of L-carnosine is crucial to abrogate the toxical effect of acetaminophen on the hepatic and kidney tissues. We previously reported that combined treatment with acetaminophen and L-carnosine possesses strong antioxidant activities via the glutathione system, superoxide dismutase, and catalase activities [23].

In conclusion, this study demonstrates that the pretreatment of rats with combined therapy of acetaminophen and L-carnosine prevented the comorbidity (anxiety) associated with NP. The combination of acetaminophen with L-carnosine also prevented nephrotoxicity and hepatoxicity which are the common negative effect of the use of acetaminophen.

NP (neuropathic pain); CCI (chronic constriction injury); CDS (comorbid depressive symtoms); TWL (tail withdrawal latency); H&E (hematoxylin and eosin); LDM (light and dark maze); EZM (elevated zero maze); ROS (reactive oxygen species)

COMPETING INTERESTS

The authors declare that there is no conflict of interest

FUNDING

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

ACKNOWLEDGEMENT

We like to appreciate Oluwadamilare Lanre Fogabi, and Olarinoye Zainab for their contributions to this study.

AVAILABILITY OF DATA AND MATERIAL

The original data of this work shall be made available on a reasonable request to the corresponding author.

ETHICAL APPROVAL

All experimental procedures were approved by the University Ethical Review Committee (UERC) of the University of Ilorin (approval number: UERC/ASN/2016/369).

CONSENT FOR PUBLICATION

Not applicable

AUTHOR CONTRIBUTIONS

B.V.O., R.T., and A.O.B. conceived and designed the research. M.O., A.M.Y., and F.E. conducted all behavioural tests. F.O. carried out the histological study. A.O.B analyzed all data. B.V.O. and R.T. contributed new reagents and analytical tools. B.V.O., A.O.B., and R.T. wrote the manuscript. All authors read and approved the manuscript and no paper mill was used.

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Combined Acetaminophen and L-carnosine Treatment Prevented Anxiety-like Behaviour in Chronic Constriction Injury-induced Peripheral Neuropathy

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Abstract

Background

Methods

Results

Conclusion

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Background

Methods

Animals

Chronic Constriction Injury

Drug And Treatment Schedule

BEHAVIOURAL TESTS

Histological Study

Statistical Evaluation

Results

Discussion

Conclusion

Abbreviations

Declarations

References

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