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2 INNOSC Theranostics and Pharmacological Sciences, 2022, Vol. 5, No. 2 Dhokne et al.
triggers nitric oxide synthase (NOS) to generate reduces inflammation-related pain in
nitric oxide from free L-arginine. In this process, animal models [11-13]. Agmatine has been shown
nitrate and nitrite are stable metabolites of nitric to improve opioid analgesia and lessen diabetic
oxide, and monitoring their concentrations is an neuropathy in rats, despite the fact that it does not
excellent way to assess the homeostasis of nitric appear to be an effective analgesic for acute phasic
oxide [5]. According to immunohistochemistry pain. According to a recent clinical investigation,
research, NOS-positive cells have been discovered agmatine is effective and safe for relieving pain
in several regions of the animal and human brains, and enhancing the quality of life in individuals
including the cerebellum and brainstem [6]. with lumbar disk-associated radiculopathy.
Studies suggest that sympathetic blockade caused Pyramidal cells in the rat hippocampus and other
by surgical and chemical agents reversibly reduces parts of the brain contain agmatine [14]. Numerous
NP symptoms and that sympathetic efferent activity physiological, pharmaceutical, and behavioral
plays a significant permissive role in the emergence research suggests that hippocampus formation is
of hyperalgesia and allodynia in humans and crucial for the effective and motivating aspects of
animals suffering from NP [7].
Agmatine is an endogenous neurotransmitter pain perception. The role of agmatine in the primary
that is produced in the mammalian brain and sense of pain has been reported [15,16]. After
other tissues. It is the decarboxylated form of a peripheral nerve lesion, the proinflammatory
L-arginine and an NMDAR antagonist. It is an cytokine tumor necrosis factor-alpha (TNFα) was
inhibitor of NOS, and it binds to α2-adrenoceptors, markedly elevated in the hippocampus, and its
imidazoline (I1/I2) receptors, and serotonin administration into the hippocampus led to NP-
(5-hydroxytryptamine or 5-HT) receptors with like symptoms [17,18]. In this review, the studies
lesser affinity than NMDAR [8-10] (Figure 1). indicating how agmatine affects NP are examined
Studies have reported that agmatine is effective at along with the underlying mechanisms of action.
reducing hyperalgesia and/or allodynia in a variety We also provide data to support clinical trials that
of chronic NP models when administered spinally would demonstrate agmatine’s effectiveness as an
and systemically. Agmatine also significantly NP adjuvant or monotherapy.

Figure 1. Schematic representation of biosynthesis and metabolism of agmatine inside the mitochondria
of astrocytes. L-arginine acts as precursor molecule, which on decarboxylation by the enzyme arginine
decarboxylase, coverts to agmatine. Agmatine is then metabolized to guanidinobutyric acid by the enzyme
diamine oxidase.

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