1. Introduction
Neuropathic pain is a prevalent public health issue resulting from lesions or diseases affecting the somatosensory nervous system. A wide range of pathological conditions, including viral infections (e.g. HIV, Herpes simplex, Varicella zoster), metabolic disorders (such as diabetes), stroke, physical trauma to the central or peripheral nervous system, and drug-induced toxicity, can precipitate neuropathic pain (Treede et al., 2008). The common clinical manifestations include hyperalgesia and allodynia. Recent studies have indicated that nearly half of the affected patients do not receive adequate treatment due to the limited efficacy of current analgesics and a lack of comprehensive understanding of the underlying pathophysiological mechanisms (Salat et al., 2018). Therefore, elucidating the molecular mechanisms of neuropathic pain and identifying novel or repurposed therapeutic agents for this condition is crucial.
Emerging evidence suggests that oxidative and nitrosative stress, often accompanied by inflammation, plays a central etiological role in neuropathic pain (Mallet et al., 2020). Under pathological conditions, persistent glutamate release from primary afferent neurons leads to the overactivation of N-methyl-d-aspartate (NMDA) receptors, resulting in a subsequent calcium influx. Elevated intracellular calcium levels activate neuronal nitric oxide (NO) synthase and other downstream signaling pathways, resulting in increased neuronal excitability and heightened pain sensitivity (i.e. hyperalgesia and allodynia). L-arginine, a semi-essential amino acid, is a precursor of both NO and glutamate in these signaling cascades. Synthesized from citrulline or derived from protein catabolism, L-arginine also contributes to insulin and growth hormone (GH) (Ong et al., 2021; Qureshi et al., 2022; Rondón et al., 2018).
GH is well-known for its critical role in growth and metabolic regulation; however, it also exhibits a range of physiological functions beyond these domains. Insulin-like growth factor 1 (IGF-1), which GH stimulates to release, regulates neural activity. Recent research has implicated the GH/IGF-1 axis in the modulation of nociceptive (Lin et al., 2016; Manzano-García & Gamal-Eltrabily, 2017). Administration of GH or GH-releasing hormone alleviates mechanical and thermal hypersensitivity, and GH treatment promotes axonal regeneration following peripheral nerve injury in rats (Liu et al., 2017; Lopez et al., 2019). Clinical observations have also reported GH abnormalities in some patients with neuropathic pain, and GH therapy has demonstrated benefits in conditions, such as fibromyalgia and chronic low back pain. Additionally, ghrelin, a GH-releasing peptide, exhibits antinociceptive effects in both inflammatory and neuropathic pain models by modulating the endogenous opioid system, inflammatory mediators, and oxidative stress. The involvement of the GH/IGF-1 axis in painful conditions, including inflammatory and rheumatic diseases, has been documented (Cuatrecasas et al., 2012; Dubick et al., 2015).
Despite this growing body of evidence supporting the role of GH in pain modulation, its analgesic efficacy in neuropathic pain models caused by peripheral nerve injury remains insufficiently understood (Liu et al., 2017). Given that peripherally administered GH can influence central nervous system activity in both animal models and human subjects (Xu et al., 2020), we hypothesized that GH may offer new therapeutic potential as a repositioned drug for neuropathic pain. This study aimed to examine the analgesic effects of GH, both alone and in combination with L-arginine, L-NAME, or glutamate, in a rat model of sciatic nerve injury, and to explore the potential involvement of oxidative stress, glutamatergic, and NO pathways in mediating these effects.

2. Materials and Methods

Experimental animals
Male albino Wistar rats, weighing 200-250 g, were purchased from the Laboratory Animal Breeding Center of the Iran University of Medical Sciences and kept under a 12:12 h light: Dark cycle (light on between 7:00 AM and 7:00 PM) at 20–25 °C and a humidity of 50%–60%. Food and water were provided ad libitum. All tests were conducted between 10:00 AM and 2:00 PM. Animals were randomly assigned to the experimental groups (n=8 per group). Caregivers were included in the grouping. They have been checked daily for animal health and underwent regular physical examinations. 

Pain induction
Neuropathic pain was induced using the chronic constriction injury (CCI) model of the sciatic nerve, (Bennett & Xie, 1988). Briefly, rats were anesthetized via intraperitoneal (IP) injection of ketamine (100 mg/kg) and xylazine (15 mg/kg). Following adequate anesthesia, an incision was made along the left thigh, parallel to the iliac crest, to expose the sciatic nerve. Four loose ligatures were then placed around the nerve proximal to its trifurcation using 4-0 chromic gut sutures, ensuring that blood flow was not completely obstructed. This procedure reliably produces behavioral signs of neuropathic pain, including hyperalgesia and allodynia.

Drugs and treatment
The animals were randomly assigned to ten experimental groups (n=8 per group). The experimental protocol was conducted in two phases.
Study 1: Determining the analgesic effect of different doses of IP administration of growth hormone. 
Group I: Control (untreated)
Group II: Vehicle (normal saline (NS) + CCI)
Groups III and IV: The group received GH (0.3 or 0.6 mg/kg)+CCI
Behavioral tests were performed two weeks after CCI surgery and 30 minutes after IP administration of GH or NS.
Study 2: Investigating the relationship of NO and glutamate in inducing analgesic effects of GH
Group V: CCI+L-arginine (500 mg/kg)
Group VI: CCI+L-NAME (20 mg/kg)
Group VII: CCI+glutamate (1000 nmol)
Group VIII: CCI + GH (0.3 mg/kg) + L-arginine (500 mg/kg)
Group IX: CCI+GH (0.3 mg/kg)+L-NAME (20 mg/kg)
Group X: CCI+GH (0.3 mg/kg) + glutamate (1000 nmol)
Drug preparation and administration
All drugs used in this study, including L-arginine, L-NAME, and glutamate (powder form), were purchased from Sigma-Aldrich (St. Louis, MO, USA) and freshly dissolved in NS before administration. Recombinant human GH (GH; ab116162) was provided as a gift. L-arginine, L-NAME, and glutamate were administered as a single IP injection in a 0.5 mL (Devesa et al., 2012; Khaki et al., 2007; Tuffaha et al., 2016).

Behavioral assessments
Before actual experimental sessions, animals were handled and habituated to an open Plexiglas chamber for 30 minutes. All behavioral tests were performed 14 days before and after CCI induction.
Mechanical nociception (mechanical allodynia) has been assessed using von Frey filaments (4.56, 4.74, 4.93, 5.07, 5.18, 5.46, and 5.88) based on a previously described method (Carrasco et al., 2018). Each filament was placed upright on the mid-plantar region of the hind paw with adequate force to cause slight bending against the rat paw and held there for 3 s. Withdrawal responses were measured by sequentially increasing and decreasing stimulus strength. The Dixon nonparametric test assessed mean withdrawal threshold (Naik et al., 2006).
Thermal hyperalgesia was determined using the Hargreaves apparatus (model 7370; Ugo Basile, Comerio, Italy) (Cheah et al., 2017). For this purpose, each rat was placed in a Plexiglass cage, and a thermal beam was applied to the plantar hind paw. Withdrawal latency was automatically recorded from the start of radiation to the point at which the rat moved or raised its foot. To avoid tissue damage, the cutoff was set at 25 s. Three trials were given at least 1 minute apart, and the average values were calculated for statistical analysis. 
The reaction to noxious mechanical pressure (mechanical hyperalgesia) was evaluated using the pressure withdrawal test (Randall-Selitto test) (Santos-Nogueira et al., 2012). Therefore, the rats were covered with a towel, and an increasing force (48 g/s) was applied to the plantar surface of the hind paw until a withdrawal response occurred. If the rats did not withdraw, the machine automatically terminated at 1000 g (25 in-scale units). Two trials were performed at least 1 minute apart, and the average values were calculated for statistical analysis. 

Biochemical assessment of enzymes related to oxidative stress
The current assay examined the potential effects of IP administration of GH on the activity of enzymes associated with oxidative stress in plasma. Immediately after the completion of behavioral assessments, the animals were deeply anesthetized with a mixture of ketamine and xylazine, and blood samples were obtained by cardiac acupuncture. Plasma samples were prepared by centrifuging the blood samples at 700-1000×g for 10 minutes at 4 °C. Then, the surface plasma was removed using a micropipette and stored in a freezer at 80 °C. The activities of enzymes involved oxidative stress, including glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), and lipid hydroperoxides (LOOHs) were measured in plasma samples using the following kits and instructions: GSH/GSSG Ratio Detection Assay Kit (Fluorometric—Green ab138881), GPx Assay Kit (Colorimetric ab102530), SOD Assay Kit (Colorimetric CM706002), CAT Activity Assay Kit (Colorimetric/Flurometric ab83464), and Lipid hydroperoxide Assay Kit (Colorimetric ab133085).

Statistical analysis
The results are presented as Mean±SEM, with P<0.05 considered statistically significant. Two-way analysis of variance (ANOVA) and the Newman-Keuls test were used to evaluate significant differences between groups for behavioral test data. One-way analysis of variance followed by Tukey's post hoc test was used to determine whether there were significant differences in the levels of enzymes involved in oxidative stress among the groups. All statistical analyses were calculated using SPSS software, version. 20.

3. Results

Effect of GH on pain-related behaviors
The results of behavioral tests indicated that a single IP injection of GH at doses of 0.3 and 0.6 mg/kg significantly alleviated pain-related behaviors, including mechanical allodynia and thermal and mechanical hyperalgesia, in the ipsilateral hind paws of CCI rats.
In the von Frey test, paw withdrawal thresholds in rats treated with 0.3 mg/kg and 0.6 mg/kg GH were 6.3±0.5 g and 5.9±0.5 g, respectively, which were significantly higher than those in the vehicle-treated group (4.5±0.5 g; P<0.05, F=2.7) (Figure 1).



As Figure 2 presented, the paw withdrawal response to noxious heat (radiant heat test) showed a significant difference between the animals receiving GH (0.3 and 0.6 mg/kg) and NS (P<0.001, F=2.5). In the plantar test (thermal hyperalgesia assessment), GH administration significantly prolonged withdrawal latency. The 0.3 mg/kg and 0.6 mg/kg GH groups had mean latencies of 10.37±0.72 s and 11.16±0.9 s, respectively, compared to 7.98±0.44 s in the saline group.



In the Randall–Selitto test (mechanical hyperalgesia assessment), GH-treated animals showed significantly higher withdrawal thresholds compared to the saline group (P<0.01, F=3.4). The mean threshold in animals receiving 0.3 mg/kg GH was 9.91±0.41 g, and that for those receiving 0.6 mg/kg GH was 10.5±0.39 g. In contrast, the saline-treated group had a threshold of 7.85±0.4 g (Figure 3).



Involvement of the glutamatergic and NO pathways
The analysis revealed that pretreatment with 0.3 mg/kg GH abolished the nociceptive effects of L-arginine (500 mg/kg) (Figure 4). In all behavioral tests, a significant difference (P<0.01, F=2) was observed between the GH + L-arginine and NS + L-arginine groups. No significant difference was observed between the mean of the NS +L-arginine and L-arginine groups.



Figure 5 shows the pretreatment outcome with 0.3 mg/kg of GH on the antinociceptive effect of L-NAME (20 mg/kg). Post hoc tests indicated that pretreatment with 0.3 mg/kg of GH enhanced the antinociceptive effect of L-NAME. A significant deviation was observed between the GH + L-NAME and NS + L-NAME treated groups (P<0.05, F=2.8). No significant difference was observed between the mean of the NS + L-NAME and L-NAME groups. The mean withdrawal latencies of the von Frey filament, radiant heat, and Randal-Selitto tests were 12.1±0.5 g, 11±0.5 s, and 11.5±0.58 g, respectively, in the GH + L-NAME group. The mean response rates were 10.3±0.5 g, 8.9±0.2 s, and 9.8±0.28 g, respectively, in the NS and L-NAME-treated groups.



Statistical analysis indicated that pretreatment with GH (0.3 mg/kg) significantly reduced the pronociceptive effect of glutamate (1000 nmol), suggesting a modulatory interaction between GH and the glutamatergic system (P<0.01, F=3) (Figure 6). 



No significant difference was observed between the mean of NS±glutamate and glutamate group. The withdrawal responses to von Frey filaments, radiant heat, and Randal-Selitto tests were 7.8±0.48 g, 12±0.45 s, and 10±0.28 g, respectively, in CCI rats treated with GH. The data were 4.8±0.2 g, 8.53±0.34 s, and 6.5±0.3 g in the NS and glutamate-treated groups.

Effects of GH pretreatment on oxidative factors in CCI rats
CCI of the sciatic nerve significantly induced oxidative stress, as evidenced by marked alterations in plasma oxidative markers compared to the control group (P<0.001, F=4).
CCI increased plasma lipid peroxidation levels. Also, it reduced SOD, CAT activity, and GSH, as well as GPx, in plasma. Administration of GH (0.3 mg/kg) significantly improved oxidative impairment by reducing lipid peroxidation levels (P<0.01, F=3.7), restoring GSH, GPx, and SOD levels (P<0.01, F=11, F=10.52, F=5), and increasing CAT activity (P<0.01, F=5) in plasma compared to NS -treated rats (Table 1).



Table 1 shows that injection of L-NAME (20 mg/kg) with and without GH injection (0.3 mg/kg) significantly increased CAT activity (P<0.01, P<0.001, F=4.78) and ameliorated lipid peroxidation levels (P<0.001, P<0.01, F=3). Also, restored GSH (P<0.001, F=3.2), GPx (P<0.001, P<0.01, F=5.2, F=3), and SOD (P<0.001, F=4) in plasma compared to NS -treated rats. Although injecting the L-arginine (500 mg/kg) and glutamate (1000 nmol) had the same effect on oxidative stress parameters compared to the NS-treated rats, pretreatment with GH (0.3 mg/kg) altered the oxidant outcome of L-arginine and/or glutamate (Table 1).

4. Discussion
The present study demonstrated that GH treatment alleviated pain-related behaviors in the CCI model of neuropathic pain in rats. These results suggest that exogenous GH, administered at non-toxic doses, may be a promising repositioned therapeutic agent for neuropathic pain syndromes. One of the proposed mechanisms underlying this analgesic effect is the antioxidant property of GH. Our results indicate that GH administration in CCI rats enhances systemic antioxidant capacity and improves the balance between oxidants and antioxidants in the blood.
Additionally, our results highlight the involvement of the glutamatergic system and NO pathway in the analgesic effects of GH (specifically Genotropin). The CCI model is widely used to replicate human-like neuropathic symptoms in rats, with peak pain behaviors observed two weeks post-surgery, gradually subsiding over the following weeks (Austin et al., 2012; Medeiros et al., 2021). Consistent with previous reports, our behavioral assays confirmed the development of both mechanical allodynia and thermal hyperalgesia in CCI-treated animals.
The effects of GH on growth and metabolism are well-established, and experimental evidence supports the ability of exogenous GH to cross the blood-brain barrier via capillary transport (Cheah et al., 2017). However, long-term GH therapy is associated with side effects, such as weight gain, transient fever, and hyperglycemia. To minimize these risks, we employed acute administration of low GH doses, guided by prior studies (Devesa et al., 2012; Liu et al., 2017; Tuffaha et al., 2016). Our data showed that systemic administration of GH at 0.3 mg/kg and 0.6 mg/kg was equally effective in reducing tactile allodynia as well as mechanical and thermal hyperalgesia. These results are consistent with prior research demonstrating the antinociceptive effects of GH in conditions, such as fibromyalgia, rheumatic diseases, and inflammatory disorders (Bianchi et al., 2017; Cuatrecasas et al., 2012; Dubick et al., 2015). 
GH has been implicated in peripheral sensitization processes, and although the precise mechanisms remain unclear, both GH and its mediator IGF-1 play roles in nociceptive processing via their neuronal receptors (Dussor et al., 2018).
It has been reported that IGF-1 exacerbates nociception through activation of its receptor, transient receptor potential cation channel subfamily v member 1 (TRPV1), and T-type calcium channels, whereas GH may mitigate hypersensitivity by downregulating IGF-1 receptor signaling. Dysregulation of IGF-1 pathways is associated with the development of chronic pain, and antagonizing IGF-1 signaling or neutralizing IGF-1 has been shown to reduce pain-related behaviors (Chen et al., 2021; Takemura et al., 2021). Therefore, GH treatment may attenuate mechanical and thermal hypersensitivity in inflamed conditions by downregulating IGF-1 receptor activity (Rhodin et al., 2014; Xu et al., 2020).
Our biochemical analyses revealed that GH administration modulated plasma levels of oxidative stress markers in CCI rats. CCI treatment significantly increased the levels of lipid peroxidation enzymes and decreased the levels of antioxidant enzymes, such as SOD, CAT, GSH, and GPx. GH treatment reversed these alterations, enhancing antioxidant capacity and restoring the levels of antioxidant enzymes (Carrasco et al., 2018; Liu et al., 2017; Xu et al., 2020).
Antioxidant enzymes neutralize reactive oxygen species (ROS) and other free radicals by reducing their energy or donating electrons, thereby stabilizing them. These enzymes disrupt oxidation chain reactions, thereby limiting cellular damage. Although ROS play essential roles in aerobic metabolism, their overproduction leads to oxidative stress. The body's antioxidant defense system, including enzymatic components (e.g. SOD, GPx, CAT) and non-enzymatic molecules (e.g. GSH), plays a critical role in mitigating ROS-induced damage (Lin et al., 2016). 
Under physiological conditions, free radicals, such as the superoxide anion, hydrogen peroxide, and hydroxyl radicals, are produced during mitochondrial respiration and scavenged by the intracellular antioxidant system. NO, synthesized from the amino acid L-arginine, is another reactive molecule that participates in redox signaling. However, excess NO reacts with superoxide to form peroxynitrite, a potent oxidative agent implicated in neuroinflammation and neuropathic pain (Areti et al., 2014; Carrasco et al., 2018; Naik et al., 2006).
Peripheral nerve injury disrupts cellular homeostasis, increases oxidative and nitrosative stress, impairs mitochondrial function, and activates microglia, all contributing to pain hypersensitivity (Mallet et al., 2020). In this study, GH treatment significantly reduced lipid peroxidation and restored GSH, GPx, and SOD levels. Previous research has shown that GH reduces oxidative stress and modulates NO production via IGF-1 signaling. NO itself has been reported to stimulate GH-releasing hormone, thereby influencing GH secretion, suggesting a bidirectional regulatory relationship. As GH modulates the L-arginine/NO pathway, it may exert analgesic effects by scavenging reactive oxygen and nitrogen species (Barabutis et al., 2011; Castillo-Padilla et al., 2012; Huang et al., 2017).
GH may also interact with glutamatergic neurotransmission. NMDA receptors are present at presynaptic terminals and modulate neurotransmitter release (Ramis et al., 2013). From a translational perspective, targeting NMDA receptor subtypes and downstream signaling may provide novel therapeutic strategies for chronic pain management.
Supporting this mechanism, we found that co-administration of L-arginine or glutamate with GH in CCI rats prevented the nociceptive effects induced by these agents. Glutamate-mediated NO production in neurons leads to the release of pro-inflammatory mediators, such as prostaglandins, leukotrienes, and substance P, ultimately sensitizing nociceptors. Excessive NO and peroxynitrite production leads to the overstimulation of glutamate receptors and central sensitization, key processes in the pathogenesis of neuropathic pain. GH pretreatment likely reduces NO production, thereby mitigating L-arginine- and glutamate-induced nociceptive responses (Chacur et al., 2010; Chen et al., 2021; Cury et al., 2011; Ilari et al., 2020; Pui Ping et al., 2020).
Our results indicated that the use of L-NAME in combination with GH enhanced the analgesic effects of this NO production inhibitor. Consistent with these results, systemic administration of L-NAME, a non-specific NO synthase inhibitor, reduced allodynia and hyperalgesia in neuropathic rats. When used in combination with GH, L-NAME enhanced the analgesic effect, likely by inhibiting NO synthase and suppressing NO production (Boumezber & Yelekçi, 2023; Mukherjee et al., 2014; Rocha et al., 2020). 
Drug repositioning is a promising approach for identifying new therapeutic applications for existing drugs by leveraging their established safety and pharmacokinetic profiles. Given the complexity of neuropathic pain pathophysiology and the limited efficacy of current treatments, repositioning approved drugs offers a cost-effective and efficient strategy for developing more effective therapies (Manzano-García & Gamal-Eltrabily, 2017; Ong et al., 2021; Qureshi et al., 2022). Given the high prevalence of chronic neuropathic pain and the modest efficacy of existing treatments, our results suggest that exogenous GH may be a novel therapeutic candidate with significant clinical potential.

5. Conclusion 
In summary, our results support the therapeutic potential of GH in neuropathic pain through multiple mechanisms, including modulation of oxidative stress and involvement of glutamatergic and NO signaling pathways. Given its established safety profile at low doses, GH may be a promising candidate for drug repurposing in the management of neuropathic pain.

Ethical Considerations

Compliance with ethical guidelines
This study was approved by the Ethical Committee of Iran University of Medical Sciences, Tehran, Iran (Code: IR.IUMS.AEC.1402.057). The experiments adhered to the guidelines of the Committee for Research and Ethical Issues of the International Association for the Study of Pain. 

Funding
This study was supported by a grant from the Physiology Research Center of Iran University of Medical Sciences, Tehran, Iran.

Authors' contributions
All authors contributed equally to the conception and design of the study, data collection and analysis, interception of the results and drafting of the manuscript. Each author approved the final version of the manuscript for submission.

Conflict of interest
The authors declared no conflict of interest.

Acknowledgments
Fred Nyberg, Uppsala University, Sweden, is acknowledged for advisory assistance.





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