Dual Inhibition and Optogenetic Regulation Targeting COX/5-LOX and TRPV1-Mediated Sensitization in the Neospinothalamic Pathway

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Tayfun Baser, Mustafa Saygin

Volume 9 · Issue 3 · pp. 632–652

Received: 20251214  Accepted: 20260914  Published: 2026-09-30

Abstract

The aim of this study is to elucidate the molecular sensitization mechanisms in the neospinothalamic pathway and to highlight that the limitations of current single-target therapies can be overcome with the novel experimental method of optogenetics. This study examines the neurophysiological dynamics, molecular basis, and novel therapeutic strategies involving optogenetics for pain perception within the neospinothalamic pathway, which is responsible for fast and localized pain transmission. During transduction, the initial phase of the pain signal, nociceptors (A-delta and C fibers) become sensitized by arachidonic acid metabolites released following inflammation. A key role in this sensitization is played by prostaglandins and leukotrienes, which are produced by the cyclooxygenase and 5-lipoxygenase enzymes. These molecules modulate the transient receptor potential vanilloid-1 ion channels, which respond to thermal and chemical stimuli, thereby increasing nociceptor excitability and leading to depolarization. The resulting electrical signal passes through a modulation phase in the dorsal horn of the spinal cord, culminating in perception in the thalamus and somatosensory cortex. It is suggested that future therapeutic strategies should focus on dual inhibitors that simultaneously target the cyclooxygenase and 5-lipoxygenase enzymes, alongside transient receptor potential vanilloid-1 antagonists, to provide more comprehensive analgesia.

Keywords: Neospinothalamic Pathway; Nociception; COX; 5-LOX; TRPV1; Optogenetic

Introduction

Pain is an experience that results from the pathological transformation of neurophysiological processes, significantly diminishing the quality of life.1 Sensitization along the neospinothalamic tract, the primary axis for pain signal transmission, plays a pivotal role in pain pathogenesis.2

The molecular basis of this sensitization is formed by mediators produced following inflammation via the enzymes Cyclooxygenase (COX) and 5-lipoxygenase (5-LOX).3 These mediators hyperactivate the transient receptor potential vanilloid-1 (TRPV1) ion channels on nociceptors, thereby lowering the pain threshold.4

Current single-target pharmacological approaches are often inadequate and associated with side effects when faced with this multifaceted pathophysiology. This necessitates the development of synergistic and innovative strategies that can simultaneously target multiple critical pathways.5 Furthermore, optogenetic applications may hold a crucial role in managing pain processes. 6

The purpose of this study is to elucidate the significance of dual inhibition in COX/5-LOX-mediated pain within the neospinothalamic pathway and to develop target-specific analgesia strategies by utilizing the advanced technique of optogenetic regulation.

Material and Method

The literature search for this review was conducted using the PubMed, Scopus, and Web of Science databases, covering publications from inception to the present day. The keywords used, in both Turkish and English, included: "pain," "neospinothalamic tract," "transduction," "transmission," "modulation," "perception," "A-delta fibers," "transient receptor potential vanilloid-1 ion channels (TRPV1)," "Cyclooxygenase (COX)," "5-lipoxygenase (5-LOX)," and "optogenetics" both individually and in combination. The primary focus of the selected studies was the neurophysiological dynamics of pain transmission and the key molecular alterations involved. Furthermore, this work aims to conduct a detailed examination of the mechanisms underlying the sensory-discriminative aspect of pain perception, with a specific focus on the unique role of the neospinothalamic tract. It is of significant importance to concretely express the neurophysiological signal transmission dynamics, especially the activation of A-delta fibers within the neuronal circuits forming the neospinothalamic tract and the specific synaptic interactions in the dorsal horn. Accordingly, the study aims to comprehensively elucidate the role of specific receptors, ion channels, and mediators involved in the regulation of these signal transmissions. This selective focus will enable a clearer identification of pharmacological and therapeutic targets for fast and localized pain transmission, an area gaining increasing importance in modern pain research.

A total of 380 references were identified during the initial search, and after removing 112 duplicate records retrieved across the different databases, 268 articles were screened at the title and abstract level. Studies that were not directly relevant to the core topic or lacked a sufficient neurophysiological and molecular foundation (n = 114) were excluded, leaving 154 references for full-text eligibility assessment. Following a detailed evaluation against criteria focusing on sensitization mechanisms, dual inhibition, and optogenetic neuromodulation, 50 studies were excluded due to a lack of experimental molecular or physiological data or target-specific mechanism analyses. Ultimately, 104 final references were included in this review to model and synthesize neospinothalamic pain mechanisms and their optogenetic regulation. The final literature search was performed on June 10, 2025 (Table 1).

Overview of the Pain Phenomenon

Pain, experienced as both an emotional and sensory process, can be defined as an unpleasant, life-quality-diminishing sensation and experience that is associated with actual or potential tissue damage.7 The experience of pain, which is influenced by both physical and psychological factors, is a phenomenon perceived through complex mechanisms generated by the peripheral nervous system, which are not yet fully elucidated.8 The stimulus, initiated by the receptor potential in nociceptors, travels through an electrophysiological flow to the dorsal horn of the posterior root ganglia, where it is modulated. The signals, having acquired a different characteristic through modulation, then arrive at the thalamus and are finally evaluated in the upper brain centers, leading to the perception of pain.9

Table 1. Literature Selection Process

Flowchart State Process Details Number of References (n)
Identified references Keyword search conducted via PubMed, Scopus, and Web of Science databases 380
Duplicate references Elimination of duplicate articles retrieved from different databases 112
Screened references Records screened at the title and abstract level with a focus on "pain," "neospinothalamic tract," "transduction," "transmission," "modulation," "perception," "A-delta fibers," "transient receptor potential vanilloid-1 ion channels (TRPV1)," "Cyclooxygenase (COX)," "5-lipoxygenase (5-LOX)," and "optogenetics" 268
Excluded references Exclusion of studies not directly relevant to the topic or lacking adequate neurophysiological and molecular foundation 114
Eligible references References retrieved for full-text assessment and evaluated according to "neospinothalamic tract", "pain", "sensitization mechanism", "dual inhibition", and "optogenetic neuromodulation" criteria 154
Ineligible references Studies containing purely clinical observations rather than experimental molecular/physiological data or lacking target-specific mechanism analyses 50
Final references Final number of references included in the review for the modeling and synthesis of neospinothalamic pain mechanisms and optogenetic regulation 104

The phenomenon of pain is a sensory and emotional process; besides being an aversive experience that impairs both physical and psychological well-being, it is also a harbinger of numerous dysfunctions.10 Neurons, neurotransmitters, and receptors concentrated in different brain regions, primarily the Ventral Tegmental Area (VTA) and the Nucleus Accumbens (NAc), play significant roles in pain perception. Furthermore, there are notable interconnections, especially neuronal networks, among the brain regions highlighted in pain perception.11 Within the brain regions actively functioning in pain perception, excitation and inhibition mechanisms work in an integrated manner. Recent studies demonstrate that the regions involved in the perception of pain and other sensations acquire functional properties by forming complex connectivities.12 It is believed that the cerebral cortex and the subcortical regions are the final destination of the pain-perceiving mechanisms through these connectivities.13

A compelling study regarding pain, which is an integrity formed by the connectivities among numerous neuronal, hormonal, molecular, and neurophysiological factors, has been conducted with nitric oxide (NO). The role of NO in pain perception, even though its mechanism is not yet fully understood, clearly highlights the importance of molecular investigation.14

The transmission of pain signals occurs via the neospinothalamic and paleospinothalamic tracts, which exhibit both anatomical and physiological differences.15 The Paleospinothalamic tract possesses an evolutionarily primitive characteristic. This tract transmits the emotional, autonomic, and general awareness dimensions of pain. These are typically slow, dull, and poorly localized types of pain.16 The Neospinothalamic tract has a highly developed structure and, unlike the paleospinothalamic tract, mediates the transmission of fast, sharp, and precisely localized pain sensations. The neospinothalamic tract is the main transmission system that provides projection to specialized sensory cortical areas.17

The neospinothalamic tract rapidly transmits the pain signal to the Ventral Posterior Lateral Nucleus (VPL) of the thalamus and then to the sensory cortex. This enables the swift understanding of the exact location and character of the pain. The paleospinothalamic tract transmits the pain signal through complex pathways to the reticular formation, Periaqueductal Gray Matter (PAG), and the Medial Thalamic Nuclei (MDN). The painful stimulus is then relayed from these regions to the limbic system and the prefrontal cortex (Figure 1).

Figure 1. Comparison of the neospinothalamic and paleospinothalamic pathways

Nociceptors

Nociceptors are the pain receptors that generate stimuli via the necessary changes in receptor potential for activations referred to as nociception.18 Not all pain is attributable to physical factors; it can also arise psychologically. Therefore, not all pain originates through nociception, but every nociceptive process results in a pain response or experience. Pain resulting from nociception is inhibited by the supraspinal antinociceptive system (Figure 2).

Nociceptors are generally categorized into two groups based on the nerve fibers that innervate them: nociceptors innervated by A-delta fibers and those innervated by C-fibers. A-delta fibers receive mechanical and thermal stimuli that generate pain sensations, while C-fibers receive mechanical, thermal, and chemical stimuli, transmitting them up to the neocortex. Nociceptors innervated by C-fibers are called polymodal receptors because they respond to all three types of stimuli: mechanical, thermal, and chemical.19 Mechanical, thermal, and chemical stimuli that reach the upper regions of the Central Nervous System (CNS) are those that have been modulated in the spinal cord and are ready for evaluation in the cortex and various brain regions. There is a threshold value that must be exceeded for all stimuli to generate a pain sensation, and once this threshold is surpassed, all stimuli acquire a noxious stimulus character.20 Consequently, with the generation of the resulting depolarization wave, mechanical, thermal, and chemical stimuli are converted into electrical impulses. This conversion stage in pain perception is known as transduction. An example of transduction is the depolarization that occurs in nociceptors at a temperature of +43 0C with a thermal stimulus.21

The conversion of mechanical, thermal, and chemical stimuli into an electrical signal is a multifunctional mechanism. Here, the activation and inhibition reactions of important hormones and neuropeptides such as potassium, serotonin, bradykinin, histamine, prostaglandins, nerve growth factor (NGF), and substance P significantly contribute to this conversion.22

There are many types of stimuli that alter the receptor potential of nociceptors found in the skin, joints, muscles, and visceral tissues.23 Some nociceptors, which are surrounded by capillaries, muscle, and connective tissue, show sensitivity to only a single type of stimulus, while others show sensitivity to multiple, different types of stimuli.24

Figure 2. Nociceptors

Neurophysiology and Molecular Mechanism of Pain

The electrophysiological flow resulting from the change in receptor potential within nociceptors is transmitted to the neocortex via A-delta and C fibers and evaluated in regions that are not yet fully understood.25 The unpleasant emotional and sensory responses resulting from this evaluation, which utilize these transmission pathways, constitute the general perspective of pain neurophysiology (Figure 3).

The transmission of pain signals to the upper brain centers occurs in four fundamental stages: transduction, transmission, modulation, and perception (Table 2).

Figure 3. Stages of pain perception

Molecular Events in the Transduction Stage

Transduction is the stage where thermal, mechanical, and chemical stimuli, when delivered to nociceptors above the threshold value, are converted into an electrical signal.26 The electrophysiological flow, generated by the formation of action potentials, is transmitted to the neocortex via afferent fibers.27 Reactions occurring at the molecular level precede this electrophysiological flow; following trauma or a painful stimulus, there is an intense release of phospholipids.28 The release of phospholipids activates arachidonic acid (AA), and the reactions become more sophisticated after this stage.29

The release of 5-LOX and COX activates numerous mediators in pain reactions. In this respect, COX holds a more significant characteristic due to its activation of prostaglandins, which are short-distance messengers. Among the known types of prostaglandins, PGE2 reaches the nociceptors, where it generates pain reactions and the electrophysiological flow (Table 3).

The pain signal, which originates during the transduction stage and acquires an electrophysiological nature, is transmitted via transmission to the neocortex, thalamus, and limbic system.30 It should be clearly emphasized here that the mediators involved in pain reactions for the paleospinothalamic tract, which is evaluated in the brainstem and requires further study, may differ.31 The primary focus here is on the neospinothalamic tract in pain transmission, and this pathway contains two crucial types of fibers: fast pain fibers and slow pain fibers.32 The electrophysiological flow resulting from action potentials during the transduction stage, mechanical and thermal noxious stimuli are transmitted by fibers referred to as fast pain fibers or A-type fibers (specifically A-delta fibers), while chemical noxious stimuli are transmitted by the unmyelinated fibers referred to as slow pain fibers or C-type fibers.19,33 C-type fibers are unmyelinated and possess the ability to carry persistent mechanical and thermal noxious stimuli.33

Cyclooxygenase Enzyme (COX): The two known forms of this enzyme are COX-1, the form expressed in normal cellular components, and COX-2, the form that emerges in inflamed cells.34,35 Nonsteroidal Anti-inflammatory Drugs (NSAIDs) typically achieve analgesia by inhibiting the COX-2 pathway. This enzyme, which is crucial for analgesia, is the primary element in the synthesis of prostaglandins during the transduction phase of pain generation.34 Nuclear Factor kappa-B (NF-κB) ensures the synthesis and regulation of cytokines, adhesion molecules, and COX-2, which initiates pain, resulting from inflammation.36

5-lipoxygenase Enzyme (5-LOX): 5-LOX acts as a pain trigger in many inflammatory and disease processes, affecting nociceptors via leukotrienes. It also plays important roles in the metabolism of AA and inflammatory fatty acids.37 NSAIDs do not exhibit anti-activity against the 5-LOX enzyme; consequently, the formation of leukotrienes cannot be inhibited by this means.38 Studies suggest that receptor antagonists of cysteinyl leukotrienes (cys-leukotrienes), which are activated by 5-LOX, exhibit an analgesic effect.39,40

Arachidonic Acid Metabolism (AA): AA is produced in the cell membrane through the catalysis of phospholipase-A2 acting on phospholipids and omega-6 fatty acids. The general mechanism of AA action occurs via 5-LOX, and therapeutic agents that act through dual inhibitory pathways on both 5-LOX and COX forms offer alternative treatment options.41 Prostaglandins activated by COX and leukotrienes activated by 5-LOX are believed to have complementary effects on pain. These two important pathways, present in pain generation (i.e., the activation of nociceptors' sensory pathways), act as fundamental mediators under the influence of AA.42

Table 2. Physiological Stages and Molecular Mechanisms of Pain Transmission

Stage Function Localization Molecular Mechanism
Transduction Conversion of noxious stimuli (mechanical, thermal, chemical) into an electrical signal Nociceptors COX, 5-LOX, AA (Arachidonic Acid), Prostaglandins, Leukotrienes, TRPV1 Ion Channels
Transmission Transmission of the electrical signal to the upper centers via afferent fibers Primary Afferent Fibers (A-delta/C), Dorsal Horn (Lamina I/V), and Spinothalamic/Spinocortical Tract Substance P, Glutamate, Aspartate, Serotonin, Norepinephrine, Endogenous Opioids
Modulation Assessment and alteration of the noxious stimulus in the spinal cord (excitation/inhibition) Spinal Cord (Dorsal Horn), Brain Stem (PAG) T-Cells, Substantia Gelatinosa (SG), Endogenous Opioids
Perception Perception of the transmitted stimulus in the upper centers, experienced emotionally and sensorially S-I and S-II, Thalamus (VPL/VPM), Limbic System (NAc, Amygdala) Substance P, Neurokinin-A, Glutamate, Aspartate

In the transduction stage of pain sensation, mediator molecules such as prostaglandins and leukotrienes, released due to cell damage or inflammation, play a crucial role. The COX and 5-LOX enzymes, involved in the synthesis of these molecules, increase the peripheral sensitivity of nociceptors and lower the pain threshold. These molecular events have a complex relationship with the primary afferent fibers that are critical for signal transmission in the neospinothalamic tract.43

A-delta Fibers

The effect of prostaglandins and leukotrienes on A-delta fibers, which form the basis of the neospinothalamic tract, is more limited compared to C fibers. A-delta fibers are associated with mechanical and thermal stimuli. The activation of these fibers primarily transmits fast and sharp pain. However, in conditions of severe inflammation, COX and 5-LOX products can indirectly lower the threshold of A-delta fibers as well, thereby intensifying fast pain transmission.44

C-Fibers

Pro-inflammatory mediators, such as PGE2 produced by the COX and 5-LOX enzymes, primarily activate receptors (like TRPV1) located at the terminals of C fibers . This activation leads to the generation of chronic or slow pain, resulting in an increase in signals originating from C fibers, which generally contribute to the paleospinothalamic tract, thereby causing chronic or persistent pain.45 Consequently, although the COX and 5-LOX systems influence the sensitivity of both fiber types, they determine the initial intensity of the pain signal, particularly through their strong effects on C fibers. These signals subsequently diverge in the spinal cord into the neospinothalamic and paleospinothalamic tracts, forming both the fast-sensory and slow-emotional components of the pain experience.46

Table 3. Molecules Involved in Pain Neurophysiology

Metabolic Pathway Enzyme Function Role in Pain Mechanism Target
COX Pathway COX-2 PGE2 release Lowers the nociceptor threshold, increasing sensitivity (Sensitization) Gs-protein Coupled Receptors
5-LOX Pathway 5-LOX Leukotriene release Triggers neutrophil migration, enhances inflammation, and directly/indirectly activates nociceptors Leukotriene Receptors
Combined COX and 5-LOX Pathway PGE2 TRPV1 Ion Channel Modulation Lowers the activation threshold of TRPV1 to thermal and chemical stimuli TRPV1 Ion Channel

Role of TRPV Ion Channels in Transduction

The transient receptor potential vanilloid (TRPV) ion channels are of central importance in the detection of pain signals by primary afferent nociceptors. Among the members of the TRPV family, TRPV1 in particular is abundantly found at nociceptive terminals and initiates transduction by responding to thermal (above +43 0C), chemical (vanilloids like capsaicin), and acidic stimuli.47 The activation of these channels triggers an influx of intracellular Ca++ ions, thereby initiating depolarization and paving the way for the generation of an action potential. TRPV1 can also be modulated by pro-inflammatory mediators produced by the COX and 5-LOX enzymes. This modulation increases the channel's sensitivity, leading to a lowered pain threshold during inflammation.Although both the A-delta and C fibers involved in the neospinothalamic tract transmission express TRPV channels, due to the polymodal nociceptor nature of C fibers, TRPV1 channel activation plays a more dominant role in chemical and thermal pain transduction.48

Molecular Relationship between Pungency and Thermal Sensation

Capsaicin, the main active ingredient in chili peppers, is not perceived solely as a chemical substance; it also activates the TRPV1 channel on nociceptors, thereby generating a physical sensation of heat. The TRPV1 channel is a polymodal receptor that responds to physical temperatures above +43 0C and to capsaicin.49

Molecular Events in the Transmission Stage

The noxious stimuli, converted into an electrical signal, are transmitted to the upper centers via spinal afferent systems, with the active participation of A-delta and unmyelinated C-fibers.50 Focusing more closely on this event, the electrophysiological flow and the changes within this flow, which naturally occur continuously in the neuronal systems established during the transduction stage, may play a role in the modulation stage.51 This mechanism has not yet been fully elucidated, but if evaluated from the perspective of the new scientific methodology of connectivity integrity, the synapse of A and C type fibers with the dorsal root ganglion triggers the release of numerous neurotransmitters and hormones.52 The most important known mediators among these are serotonin, norepinephrine, endogenous opioids, gamma-aminobutyric acid (GABA), somatostatin, and galanin.53 It is noteworthy that endogenous opioids are also secreted, reacting or preparing for a reaction, during the process of pain generation.54 The neospinothalamic tract is the most evolutionarily advanced pathway known; it largely projects to the thalamus and is then evaluated in yet-to-be-defined regions of the neocortex.55 It is crucial to reiterate that the painful stimulus transmitted to the neocortex is transformed from what was generated in the transduction stage and is transmitted having acquired a new characteristic during the modulation stage.56

Transmission, one of the four fundamental stages of pain signal conduction, is frequently used in the literature. To ensure definitional consistency, the transmission stage in painful stimulus conduction can be clarified in two main steps. The first step after transduction consists of primary afferent transmission.57 In this stage, the generated action potential is conveyed via the primary afferent nociceptive fibers (A-delta and C fibers) to the dorsal horn of the spinal cord. This physiological process marks the initial entry of the painful stimulus or signal from the periphery into the central nervous system. The second step in pain signal transmission consists of the secondary afferent conduction system. This pathway is also referred to as the spinocortical transmission system. The actual transmission process involves the pain signal being received by T-neurons—which are the second-order neurons located in Lamina I and Lamina V of the dorsal horn—crossing the spinal cord, and projecting towards the thalamus and neocortex.58

Molecular Events in the Modulation Stage

The modulation stage of pain neurophysiology is observed in both ascending and descending pathways.59 Modulation in ascending pathways generally has a pain signal-enhancing role and is referred to as peripheral modulation. Modulation seen in descending pathways is called central modulation, where pain signals can be either amplified or attenuated.60,61

Peripheral Modulation

Modulation is the process where a noxious stimulus is evaluated in the spinal cord and undergoes various changes before being transmitted to the upper centers.62 This stage of pain neurophysiology is closely associated with cognitive processes.63 However, the mechanism of modulation is not fully understood, and various theories have been developed for it. The most important, and yet to be falsified, is the Gate Control Theory.64 It is hypothesized that the impulse arriving at the spinal cord and dorsal horn is altered and modulated there, but there is no definitive molecular or neurophysiological evidence regarding the exact pathways.65 Specific subcortical structures and the brainstem are involved in the modulation stage—that is, in the temporary changes occurring in the neuronal structures and tissues of the spinal cord—and in the perception of the painful stimulus.66

Gate Control Theory: In the posterior horn, there are groups of neurons, which are part of the sensory stimulus pathway, that are constantly inhibited. Noxious stimuli arriving via the A-delta fibers disrupt this inhibition.67 These constantly inhibited groups of neurons are the Transmission cells (T-cells). When activated by a noxious stimulus, these cells enable the opening of the neurons in Lamina II and III, also known as the Substantia Gelatinosa (SG).68 SG, which functions as an interneuron, is a component of the inhibition mechanisms during nociception processes.69 SG and T-cells, the most crucial components of the gate control system, are located within the dorsal horn. Nerve fibers originating from nociceptors innervate these areas, allowing the transmission of noxious stimuli to the upper centers. According to the Gate Control Theory, the activation (opening) of SG is enabled by the activation of the constantly inhibited T-cells.70 However, not all neural stimuli originating from nociceptors can remove the inhibition on T-cells and permit the opening of SG. Even if a stimulus occurs in the nociceptors, a certain threshold value must be exceeded for SG to open.71 Once the threshold value is surpassed, the constantly inhibitory signal pathways cease, and a different type of noxious stimulus is transformed into a new stimulus type and transmitted to the neocortex.72 SG activation is controlled by A-delta and C fibers, and the resulting stimulus, evaluated in the neocortex, is the outcome referred to as pain. It is believed that the descending pathways on the dorsal column from the supraspinal region also contribute to the modulation of the pain stimulus after the opening of SG. The Gate Control Theory explains the molecular and neurophysiological events occurring during the modulation phase of the pain perception process. Furthermore, this theory integrates and clarifies the previously proposed Pattern Theory and Specificity Theory.73

A-delta and C-fibers carry pain signals, activating the T-cell and simultaneously inhibiting the SG interneuron. A-beta fibers carry non-painful touch or pressure signals. These fibers both excite the T-cell and activate the SG interneuron. The SG functions as a gate, applying constant inhibition on the T-cell. The T-cell is the main cell that transmits the pain signal to the CNS. The activation of this cell is modulated by the SG and the fiber inputs (Figure 4).

Figure 4. Gate Control Theory

Central Modulation

Central modulation occurs in the descending pain pathways. The descending pathways achieve modulation by directly influencing signal transmission in the dorsal horn of the spinal cord, using signals received from the brain's upper centers.74 In this modulation, fibers descending from the PAG and RVM (Rostral Ventromedial Medulla) regions, primarily utilizing serotonin and norepinephrine, suppress pain transmission in the dorsal horn. However, neurons descending from the RVM can also release neurotransmitters that increase pain transmission. In this latter case, the neurons in the spinal cord become excessively activated and the pain signal is amplified.75

Unexpected Effect of Descending Modulation Pathways: Placebo

The powerful analgesic response known as the Placebo effect in the brain is typically explained by the activation of descending antinociceptive pathways and the release of endogenous opioids. Pain reduction during the placebo effect is not merely a psychological change in perception; it is a genuine biochemical and neurophysiological event.76

Functional Magnetic Resonance Imaging (fMRI) studies have shown that patients' expectations of reduced pain activate modulatory regions in the brainstem, such as the PAG, and that these regions descend to the dorsal horn to inhibit pain signal transmission.77 PAG activation can be triggered not only by opioid drugs but also by a simple expectation. This finding proves the power of the modulation system and how fundamentally cognitive factors can alter the pain experience. Anatomically, this modulation begins in the PAG, located in the brainstem, and the nerve pathways originating from it constitute the main components of the descending pain control system. The PAG does not transmit the pain signal directly to the spinal cord but activates the RVM region located in the midline. Neurons in the RVM then descend to the dorsal horn of the spinal cord, where they perform synaptic modulation.78

In the descending pathways, not only endogenous opioids but also monoamine neurotransmitters like serotonin (5-HT) and norepinephrine (NE) play a critical role.79 The pathways descending from the RVM increase neurotransmitter release in the dorsal horn, the junction point between nociceptive primary afferent neurons and secondary neurons in the spinal cord. These chemicals inhibit the upward transmission of the pain signal towards the thalamus at both the presynaptic and postsynaptic levels, primarily through inhibitory interneurons in the spinal cord.80

The endogenous opioids underlying placebo analgesia are neuropeptides such as enkephalins, endorphins, and dynorphins. These neuropeptides bind to µ-opioid receptors (MOR), which are highly concentrated on nociceptive nerve terminals and interneurons in the dorsal horn.81 MOR activation hyperpolarizes neuronal membranes, reducing neuronal excitability, and thus strongly suppressing pain signal transmission. This mechanism is biochemically identical to the analgesia provided by exogenous opioid drugs like morphine and fentanyl.82

Neurological Events Occurring in the Perception Stage

This is the stage where the impulse transmitted from the spinal cord via the nociceptive afferent pathways is conveyed to and perceived by the CNS.83 Fibers of the neospinothalamic tract reach the ventroposterolateral (VPL) and ventroposteromedial (VPM) nuclei in the thalamus, and from there, they project to the primary and secondary somatosensory cortices (S-I and S-II). This projection is the main mechanism that allows the perception of the pain's fast, sharp nature and precise localization. The contributions of neuronal activations and the released Substance P, Neurokinin-A, Glutamate, and Aspartate are known in this perception process.84 The crucial point to emphasize in the pain perception process is that a single brain region is not responsible for perception; stimuli crossing through the thalamus are perceived via the connectivities of the neocortex, NAc (Nucleus Accumbens), amygdala, and various parts of the limbic system.85 It is worth reiterating that the stimuli arriving here are those that have been altered and rendered perceptible during the modulation stage in the spinal cord. From the perspective of the scientific methodology known as connectivity integrity, pain perception—or the perception stage—constitutes the entirety of this process.86 This entirety is formed by connectivities such as neuronal connections in different brain regions, their consolidation, and the activation and/or inhibition of neurotransmitter pathways.87

In the perception phase, pain is experienced emotionally and physically, while also inducing striking changes in the neurophysiological flow.88 The fundamental mechanisms of perception emerge as a result of intervention in this flow, which leads to the conclusion that pain is also a psychological phenomenon.89 For this reason, when classifying pain, an interesting type of pain called phantom limb pain is often mentioned. Phantom limb pain can be briefly concretized with the following example: a person who has lost a leg may feel pain as if the leg were still there.90 This is due not only to psychological factors but also to physiological processes that are yet to be fully explained. Since the brain does not have an experience to understand the presence of organs, this may be one of the significant causes of phantom pain.91 However, not only the brain but also different subcortical regions may contribute to the perception stage.92 Because pain is a stimulatory feature that initiates primitive drives such as avoidance, protection, fighting, and feeding, it is important to consider that primitive neuronal regions operating in the brainstem, in addition to components like the neocortex, NAc, amygdala, and hippocampus, also play a role in pain perception.93 The perception stage gains meaning through the projection provided by the neospinothalamic tract to the upper brain centers, representing the final point where the sensory-discriminative components of the pain experience are evaluated.94

Phantom Pain and the Pain Neuromatrix

The final perception of signals transmitted by the neospinothalamic tract is one of the most complex processes in the brain. The most striking proof that pain is not merely a sensory experience but also a cognitive and emotional output is the phenomenon of Phantom Limb Pain (PLP).95 PLP is the condition, observed in 60%-80% of amputees, where a severe and realistic sensation of pain is experienced despite the physical absence of the limb. This condition, which indicates that pain is not a simple signal transmission, is explained by the "Neuromatrix Theory" proposed by Ronald Melzack.96 According to this theory, a broad neural network composed of different brain regions (thalamus, limbic system, S-I/S-II) continuously produces an output regarding the body's integrity (the neuromatrix signature). Even when the limb is lost, this matrix remains active and can generate a pain output without a pain signal input. This demonstrates that pain is actually a perception constructed in the brain and that the connectivities of the neospinothalamic tract in the cortex can be triggered independently of true physical input.97

Novel Experimental Method for Precise Control of Pain Mechanisms

The neospinothalamic tract and its sensitization mechanisms (the COX/5-LOX and TRPV1 axis), which are the focus of this review examining the neurophysiological dynamics and molecular basis of pain perception, can be analyzed more precisely using optogenetic techniques. This approach facilitates the development of new therapeutic strategies for pain in the future.98

Optogenetics

Optogenetics is a biological method formed by the combination of genetic and optical strategies that allow the control of cellular activities, particularly the efficacy of neurons, using light.99 Etymologically, the term merges "optic" (light) and "genetic" (gene-derived) elements. This method is a neuromodulation approach used to monitor and direct neural activity in living tissues and cells.100

The fundamental principle of the technique involves transferring the genes of light-sensitive proteins called opsins, derived from bacteria or algae, into the target neurons via a harmless viral vector.101 Opsins are genes that enable the formation of light-responsive ion channels that embed in the neuronal membrane, namely channelrhodopsin (ChR) and halorhodopsin (NpHR) (Figure 5).

Figure 5. The ChR and NpHR channels generated by the opsin gene

ChR, which is activated by blue light, allows the influx of cations into the cell, leading to depolarization. NpHR, which is typically sensitive to orange/yellow light, pumps chloride ions into the cell, generating hyperpolarization (Figure 6).

Figure 6. Effects of blue and yellow light on ChR-NpHR channels

In the optogenetic experimental method, excitation or inhibition can be achieved reversibly with millisecond precision by delivering light of a specific wavelength to the target neuronal population via optic fibers. Thanks to this high temporal and spatial resolution, optogenetics offers significant potential in elucidating the functioning of the complex neuronal mechanisms involved in pain transmission (Figure 7).

Figure 7. Excitation mechanism of the ChR channel and inhibition mechanism of the NpHR channel

Optogenetic Applications in the Axis of Transduction and Molecular Sensitization

The optogenetic experimental method can be utilized to mimic or control the cellular effects of molecular events occurring during the transduction stage of pain perception.102

Investigation of Nociceptor Activation

Opsin genes restricted to the TRPV1 gene promoter can be introduced specifically into the A-delta fiber populations (transmitting fast pain) and C-fiber populations (transmitting slow pain). This strategy allows for the precise triggering or inhibition of neuronal activation using light alone, without altering the intrinsic threshold of the primary afferent neurons or relying on COX/5-LOX products (Figure 8).

Figure 8. Activation of nociceptors with blue light

Mimicking TRPV1 Modulation

The Ca++ influx and subsequent action potential formation caused by TRPV1 activation can be mimicked optogenetically using ChR. This allows for the neurophysiological consequences of the COX and 5-LOX products' effect on increasing TRPV1 sensitivity to be modeled with light. Consequently, it enables the analysis of the electrical signal conversion (transduction) underlying sensitization (Figure 9).

Figure 9. Optogenetic mimicry of TRPV1 modulation

Applications in the Axis of Neospinothalamic Transmission and Modulation

The complex mechanisms of the neospinothalamic tract, which ensures the transmission of the pain signal from the spinal cord to the thalamus and cortex, can be mapped and modulated using the optogenetic method.103

Elucidation of the Gate Control Theory

The modulation stage occurring in the dorsal horn and the Gate Control Theory involve the interaction of neurons that transmit and inhibit noxious stimuli (e.g., T-cells). Optogenetics can clearly demonstrate how the pain gate opens and closes in vivo by selectively activating or inhibiting the specific neurons within these excitation/inhibition circuits using light (Figure 10).

Figure 10. Effect of blue and yellow light on T-cells

Control of Supraspinal Pathways

Studies on the upper centers where pain is perceived and on the descending antinociceptive pathways can be advanced using optogenetics. Targeting the neuronal populations in these regions with light allows for the modeling of the signal's effects on emotional and sensory responses before or after the signal reaches the perception stage (Figure 11).

Figure 11. Role of yellow light in supraspinal pathways

Therapeutic Potential of Optogenetics

The limitations of current pharmacological approaches stem from targeting a single molecular mechanism (e.g., only COX-2 or only TRPV1). Optogenetics holds the potential to revolutionize the development of next-generation therapies by overcoming these limitations.104

Unlike conventional drugs, optogenetics can minimize systemic side effects by targeting only the specific neurons that transmit the pathological pain signal. Furthermore, through customized neuromodulation, pathologically activated circuits in chronic pain conditions (e.g., in the spinal cord or the thalamocortical pathway) can be silenced using light delivered via implanted optical devices. This approach paves the way for future gene-based neuromodulation treatments involving the direct control of neural activity, complementing molecular targets such as dual inhibitors and TRPV1 antagonists (Figure 12).

Conclusion

This review highlights the critical role of the neospinothalamic pathway and its molecular sensitization mechanisms in fast, localized pain processing. Key molecular players at the transduction level—specifically COX-2, 5-LOX, and TRPV1 ion channels—collectively drive peripheral sensitization. While traditional analgesics primarily target single pathways, current preclinical literature suggests that dual COX/5-LOX inhibition, potentially combined with TRPV1 modulation, may offer a more comprehensive approach to reducing inflammatory nociceptive drive. However, further translational research and rigorous clinical trials are required to establish the safety, optimal dosing, and actual clinical efficacy of these multi-target pharmacological strategies. In parallel, optogenetics serves as a powerful experimental tool with high temporal and spatial resolution to decipher specific neuronal circuits within the neospinothalamic tract and dorsal horn networks. Although light-based neuromodulation demonstrates significant potential in preclinical models for silencing pathologically active pain pathways, its clinical translational utility remains limited by challenges in gene delivery, optical hardware implantation, and long-term biocompatibility. Future investigations should therefore focus on bridging these methodological gaps to carefully assess the realistic therapeutic scope of target-specific neuromodulation in chronic pain management.

Figure 12. Comparison of Traditional and Optogenetic Treatment Approaches in Pain Therapy

Conflict of interest statement: There is no conflict of interest among the authors.

Authors contributions: TB: Conceptualization; Data curation; Investigation; Methodology; Validation; Visualization; Writing-original draft; Writing- review & editing. MS: Validation; Writing-original draft; Critics

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