2.2. Central targets

1.1.3.2. Intensity theory

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1.1.3.3. Gate control theory

2.1. Peripheral targets

which type of sensation should be percieved [20].

grey matter, part of endogenous opioid system (modified from Patel [17]).

face decrease in inhibition of large fibres [23].

2. Target of pain: central and peripheral

Sydenham proposed that the peripheral stimulus acts as a signal whose intensity determines

Figure 2. Serotoninergic (5-HT) and adernergic modulation by the raphe nucleus and locus ceruleus. PAG—periaqueductal

Melzack and Wall recommended that second-order spinal neurons (Dorsal horn transmission cell or wide dynamic range (WDR) neuron are stimulated by sensory fibers of divergent specificity that, unpredictably fire, subject to their degree of facilitation or inhibition. Inhibitory substantia gelatinosa (SG) cells are stimulated by large sensory fibres because in dorsal horn transmission cells are triggered by both large and small diameter afferents [21]. In the substantia

Direct suppression of transmission cells by SG cells close the gate. On the other hand, the SG cells suppressive effect declines due to the amplified activity in small diameter fibres which can also be increased by the peripheral nerve damage and cause the opening of gate and also

At the peripheral terminal, pro-inflammatory mediators are released from the mast and schwann cells, macrophages and neutrophils which are resident and migrating cells, respectively, due to the injury to cells and blood vessels in return of stimuli, for example, a tissue damage or infection. Dorsal root ganglion (DRG) cells hold receptors for these mediators, which upon activation initiates a cascade of event from the intracellular kinases. In turn, receptor

gelatinosa, neuron and integrated circuits regulate the opening and closing of 'gate' [22].

The spinal primary afferents due to cell insult, such as tissue injury, inflammation or nerve injury activate the primary afferents and induce voltage gated calcium cannels (CaV) and soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) Protein-dependent release of neurotransmitters, growth factors and neuropeptides. The resident glial and migrating cells (T cells, macrophages and neutrophils) in the spinal cord along with the second-order neurons are activated by the release of these substances, which in turn release a collection of pro-inflammatory and anti-inflammatory molecules to further act on the secondorder neurons activating several protein kinases responsible for the phosphorylation of several membrane bound receptors, thus initiating and maintaining the hyperexcitable state of these neurons, and further sending the nociceptive signals to higher brain centres. The second-order neurons facilitate the excitability of dorsal horn projection neurons and scheme onto raphespinal serotonergic neurons through the bulbospinal pathway which dismiss in dorsal horn neurons [24]. In Table 2, central and peripheral pain targets are shown along with their source of cell insult/stimuli and inflammatory mediators and receptors which are and may be the future targets for pain alleviation.

#### 2.3. Pain targets with molecular mechanisms of activation and sensitization of nociceptors

In Figure 3, Nociceptors direct ion channels for generation of transduction and action potential, and a large number of receptors for inflammatory and other mediators are either coupled to ion channels or, more often, activate second messenger systems that influence ion channels.

#### 2.3.1. Transient receptor protein (TRP) channels

The transient receptor protein subfamily V member 1 is an individual receptor from the TRP (transient receptor protein) family. Other TRP individuals might be transducers of temperature boosts in different extents [26]. Capsaicin, the compound in hot pepper, opened the ion channel that grounds burning pain. Specifically, Ca2<sup>þ</sup> moves through this channel and depolarizes the cell. The TRPV1 receptor is opened by heat (>43�C) thus measured one of the transducers of noxious heat. In TRPV1 knock-out mice, the heat response is not eradicated but the mice do not display thermal hyperalgesia throughout inflammation, presenting the significance of TRPV1 for inflammatory hyperalgesia [27, 28]. Up-regulation of TRPV1 transcription during inflammation explains longer lasting heat hypersensitivity. The TRPV2 receptor in nociceptors is assumed to be a transducer for exciting heat (threshold >50�C). TRPA1 could be the transducer molecule in nociceptors reacting to frosty. It is actuated by impactful mixes, e.g. those present in cinnamon oil, mustard oil and ginger. By differentiation, TRPV3 and/or TRPV4 might be transduction molecules for harmless warmth in warm receptors and TRPM8 may transduce chilly jolts in harmless cold receptors. Despite the fact that the putative warmth transducer TRPV4 demonstrates some mechano-sensitivity, it is still in vague whether TRPV4 is included in the transduction of mechanical stimuli [29–31].



Table 2. Schematic representation of peripheral as well as central targets from the point of insult to cells, sources of cell insult and inflammatory mediators and receptors for the current and future analgesics.

Figure 3. Ion channels for transduction of thermal and mechanical stimuli and action potential generation and metabotropic receptors subserving chemosensitivity involving sensory ending of nociceptor (modified from Schaible [25]).

#### 2.3.2. Voltage-gated sodium channels and acid sensing ion channels

Type of targets Peripheral targets Central targets

DNA, RNA, HMGB1 TLRs Pro-

Source Local/resident cells Migrating

Bradykinins, 5-HT, CGRP, Prostaglandins, Lipoxygenases,

ATP Purinergic

Chemokines (e.g. CCL2, CXCL1) Chemokines

Cytokines (e.g TNF, IL-1β) Cytokines

proteinases

Schwann cells

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Inflammatory mediators and receptors

Stimulus Tissue injury, inflammation or infection Tissue injury, inflammation or nerve damage

FPS FPR1 Second-order neurons

GPCRs

Receptors

Receptors

Receptors

sP NK1 mGluR5

NGF, BDNF TRK PKA NMDA

cells (Local/ DRG)

Endothelial cells Macrophages Astrocytes T cells Keratinocytes Neutrophils Microglia Macrophages Mast cells Bacteria Neutrophils

Resident cells

analgesics

TNF, IL-1β, IL-6

Growth factors

Protein kinases

CaMK NK-1

PKC AMPA-CP

MAPK mGluR1

Chemokines Cytokines

CCL21 IFNy, IL-4, IL-10, IL-14 CCL2 Lipid mediators Cytokines Resolvins

Protectins

Lipoxins

Epoxyeicosatrienoic

ATP Epoxy fatty acids

acids

Receptors

Spinal neurons Migrating

Anti-analgesics

cells

Tetrodotoxin (TTX) hindered many voltage-gated Naþ channels and numerous small dorsal root ganglion (DRG) cells direct TTX-resistant (R) Naþ channels, notwithstanding TTXsensitive (S) Naþ channels. Both TTX-S and TTX-R Naþ channels pay to the Naþ influx during the action potential. Excitingly, inflammatory mediators pre-disposed TTX-R Naþ currents. Nociceptors are sensitized by boosted prostaglandin E2 (PGE2). This raises the likelihood that TTX-R Naþ channels likewise assume a part in the transduction procedure of poisonous boosts. SNS�/� knock-out mice (SNS is a TTX-R Naþ channel) show declared mechanical hypoalgesia, however just little shortages in the reaction to thermal incitements [32, 33]. Low pH values cause opening of acid sensing ion channels (ASICs) and are Naþ channels. In general, ASIC family comprises of six subunits (1a, 1b, 2a, 2b, 3, and 4). This is of interest because many inflammatory exudates exhibit a low pH. Protons straightforwardly initiate ASICs with ensuing generation of action potentials. The ASIC family expressed in peripheral neurons is ASIC 1b and ASIC 3 subunits which possess a high degree of selectivity in sensory neurons [34, 35].

#### 2.3.3. Receptors of inflammatory mediators (chemosensitivity of nociceptors)

The chemosensitivity of nociceptors permits inflammatory and trophic intermediaries to follow up on these neurons. Inflammatory cells and non-neuronal tissue cells are their cradles. In the activation and sensitization of neurons, two types of receptors either ionotropic (the mediator opens an ion channel) or metabotropic (the mediator activates a second messenger cascade that influences ion channels and other cell functions) are encompassed. Numerous receptors are coupled to G proteins, which signal by means of the generation of the second messenger cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), diacylglycerol and phospholipase C. The receptors are having intrinsic protein tyrosine kinase domains that associate with cytosolic tyrosine kinases and protein serine/threonine kinases [31, 36]. There are several functions of mediators, which may involve the direct activation of neurons (e.g. the bradykinin induces action potentials by itself) and/or sensitization of neurons for mechanical, thermal and chemical stimuli (e.g. bradykinin and prostaglandins increase the excitability of neurons so that mechanical stimuli arouse action potentials at a lower threshold than under switch circumstances occur). PGE2, for example, activates G protein-coupled EP receptors that cause an increase of cellular cAMP. This second ambassador actuates protein kinase A, and this pathway impacts ion channels in the membrane, prompting an improved edginess of the neuron with brought down limit and expanded action potential recurrence inspired amid suprathreshold incitement. Bradykinin receptors are of awesome interest on the grounds where bradykinin enacts various Aδ and C fibres and sharpens them for mechanical and warm boosts [37]. Freund's complete adjuvant induced mechanical hyperalgesia of the rat knee joints and thermal hyperalgesia can be reversed by the bradykinin receptor antagonists. A few reports recommend that specifically bradykinin B1 receptors are up-controlled in sensory neurons taking after tissue or nerve damage, and that B1 antagonist diminishes hyperalgesia. Up-regulation of B2 receptors during inflammation also found by some authors [38, 39].

#### 2.3.4. Neuropeptide receptors and adrenergic receptors

Receptors for a few neuropeptides have been recognized in primary afferent neurons, including receptors for the excitatory neuropeptides SP (neurokinin 1 receptors) and CGRP, and receptors for inhibitory peptides, in particular for opioids, somatostatin and neuropeptide Y (NPY) [40, 41].
