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6 INNOSC Theranostics and Pharmacological Sciences, 2022, Vol. 5, No. 2 Dhokne et al.

Table 2. Animal models of neuropathic pain
No. Name of animal model Principle Species
1. Axotomy (complete sciatic nerve Whole transection of sciatic nerve Rats
transection) [33,38]
2. Acrylamide-induced injury [39] Prolonged administration of acrylamide Rats
3. Chronic constriction injury [33,40] Four loose ligatures around the sciatic nerve Rats, mice
4. Partial sciatic nerve ligation (Seltzer Model) Tight ligation of one-third to half of the Rats, mice
[41,42] sciatic nerve
5. Orofacial pain [43] Injection of formalin, carrageenan into Rats, mice
temporomandibular joints and maxilla
6. Spinal nerve ligation [44,45] Tight ligation of L5 and L6 spinal nerves Rats
7. Spared nerve injury [46,47] Axotomy of tibial and common peroneal Rats, mice
nerves
8. Trigeminal neuralgia [48,49] Compression of trigeminal ganglion; Rats
chronic constriction injury to the infra-orbital Rats
nerve
9. Diabetes-induced neuropathy Persistent hyperglycemia-induced changes in Rats, mice
(streptozotocin-induced andgenetic models) the nerves
[50,51]
10. Weight drop or contusive spinal cord injury Dropping a weight over the exposed spinal Rats, mice
[52] cord

NMDAR [61]. Agmatine likely works on spinal hydroxylase to enhance the release of 5-HT.
imidazoline receptors to reduce pain [14]. Agmatine Furthermore, it was suggested that the production
was reported to have lessened the antiallodynic of neurotrophic chemicals by macrophages,
and anti-hyperalgesic effects in diabetic NP when activated microglia, and infiltrating monocytes
combined with an imidazoline receptor antagonist. contribute significantly to neuroinflammation.
In spinal nerve ligation animal modelswith diabetic These compounds have both pro-inflammatory
NP, agmatine also exerts an antiallodynic effect. and neuroprotective effects. It was suggested that
When all underlying causes of NP are taken into agmatine could enhance the anti-inflammatory
account, agmatine can substantially treat numerous M2 macrophage properties without boosting cell
neuropathies owing to its NMDAR antagonist, numbers. Its anti-neuropathy effectiveness may
NOS inhibitory, and anti-inflammatory effects. One possibly be due to the proinflammatory M1 and
of the pathogenic pathways that can be triggered by anti-inflammatory M2 macrophages’ induction
neuronal injury and chronic pain is the activation of the activation of axonal regeneration after
of NMDAR and NOS [62]. All isoforms of NOS, neuronal damage. The hippocampus is one of
especially the most powerful types, as well as the many regions of the brain where agmatine
NMDAR and NMDA-mediated Ca currents, is widely distributed and colocalizes with sigma
2+
have all been reported to be blocked by agmatine receptors. Sigma receptors were present in sciatic
(Figure 3). nerves [66,67] as well, and Sigma-1 receptors,
It has recently been reported that cisplatin- in particular, were crucial for controlling NP.
induced mechanical allodynia, sciatic Furthermore, some data suggest that NP may have
nerve degeneration [63,64], and dorsal root higher-than-normal hippocampal TNFα levels
ganglia cell senescence may be prevented by [68]. Sigma-1 and Sigma-2 receptor [63] agonists
agmatine. Studies indicate that agmatine’s were shown to boost TNFα production, whereas
neuroprotective and antiallodynic effects were agmatine lowered TNFα levels, indicating that
not significantly increased by L-NAME. Another inhibiting these receptors in NP-induced rats may
study demonstrated that NOS inhibitors and be beneficial. As a result, the antinociception
NMDAR antagonists [65] can activate tryptophan induced by agmatine may include the serotonergic,

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