INTRODUCTION:

Pain is a vital, physiologic, multidimensional sensory experience, which is a key early warning device, an alarm system that announces the presence of a potentially damaging stimulus.¹The Subcommittee on Taxonomy of the International Association for the Study of Pain (IASP) in 1986 defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of tissue damage, or both”.^2,3Pain is manifested as the activity of sympathicus, producing fear, anxiety, pupillary dilation, tears, tachycardia, hypertension, nausea, vomiting, sound effects, and facial expressions.⁴It may vary in intensity, quality, duration, and referral.¹

Pain is a highly personal experience that is communicated outwardly to healthcare providers, family members, and friends by verbal signals, as well as through body and facial expressions.⁵James Campbell in 1995, presented the idea of evaluating pain as the 5^th vital sign.⁶Peripheral pain mechanisms associated with odontogenic painful conditions are overall similar to the mechanisms observed in all other body parts. These similarities include the type of sensory neurons involved as well as the different molecules that play a role in these processes.^7,8,9Since algesia is a part of day-to-day clinical practice in dentistry, the aim of this article is to provide a brief overview of the various aspects of pain and its neurophysiology behind its perception.

METHODS:

Sources of information:

Several electronic databases were used to conduct a computerized search for available evidence: MEDLINE and other Non-indexed Citations, PubMed, Scopus, Google Scholar, and Evidence-based Medicine reviews like Cochrane Database of Systematic Reviews up to January 30, 2019.

Search strategy:

Terms used in this literature search were “odontogenic pain”, “dental painphysiology”, “pain biology” and “chemical mediators in dental pain”. Details for each database search are available upon request. The reference section of the identified papers was also searched in order to identify additional articles.

Search and selection process:

The articles that appeared to fulfill the requirements of this literature search were selected. For abstracts that provided insufficient information to make a selection decision, the entire article was also obtained. Also articles in the databases without proper abstracts but titles suggesting that the articles could be of relevance were selected. The references from all of the selected articles were scrutinized for articles which may not have been in the databases due to their early publication date or for any other reason.

Extracting and synthesizing of data:

The articles containing data regarding the neurophysiology of dental pain were selected. The necessary data from results of the selected studies were also taken into consideration.

AETIOLOGY OF ACUTE OROFACIAL PAIN¹⁰

There are a wide range of causes of acute orofacial pain conditions, the most common being dental pain. Dental disease of the hard tissues (caries of enamel, dentine, and cementum), and soft tissues and supporting bone (gingivitis/periodontitis) are recognized as the most common diseases to afflict the general population. The most common forms of oral pain include pulpitis, pericoronitis and periapical periodontitis. Dentine sensitivity, dry socket and trauma or infection of the orofacial tissues for the minor etiologic aspects.

CLASSIFICATION:^11,12,13

Orofacial pain can be classified as:

· Somatic

· Superficial [Skin & Mucous Membrane]

· Deep

· Musculoskeletal [Periodontium]&Visceral [Pulp]

· Neuropathic

Based on duration, pain can be classified as:

· Acute [Physiologic cause, Shorter duration, Etiology-Trauma, Surgery, Behavioral reaction seen]

· Chronic [Pathologic cause, Longer duration, Etiology not easily identified, Psychosocial changes seen]

Based on nature, pain can be classified as:

· Fast [Sharp/Pricking type, felt 0.1sec after stimulus, eg: Needle prick, transmitted by Aδ type fibers, Easy to localize]

· Slow [Burning/Throbbing type, felt>1sec after stimulus, eg: Tissue Destruction, transmitted by C type fibers, Difficult to localize]

Based on site, pain can be classified as:

· Primary - Pain at the site of stimulus

Secondary can be further classified as:

· Central - disturbance in CNS (pain is felt in the peripheral nerve distribution)

· Projected - disturbance in root of nerve (pain is felt in the same nerve distribution)

· Referred - disturbance in one nerve branch (pain is felt in different nerve branch)

Perception:

The perception of pain is a complex process initiated in the periphery by stimulation of free nerve endings by mechanical or thermal means, or by the release of chemical mediators following tissue damage.¹⁴

Pain is perceived by the following four mechanisms:^15,
16

· Transduction is the conversion of the energy from a noxious thermal, mechanical, or chemical stimulus into electrical energy (nerve impulses) by sensory receptors called nociceptors.

· Transmission is the transmission of these neural signals from the site of transduction (periphery) to the spinal cord and brain.

· Perception is the appreciation of signals arriving in higher structures as pain.

· Modulation is the descending inhibitory and facilitatory input from the brain (from trigeminal spinal nucleus, reticular formation of brainstem) that influences (modulates) nociceptive transmission at the level of the spinal cord.

Stimulation:

Pain can be elicited by multiple types of stimuli. They are classified as mechanical, thermal, and chemical pain stimuli.¹¹ (Fig.1)

Figure1: Various stimuli of nociceptors

Following a painful stimulus, if sufficient numbers of a particular typeof nociceptor are activated, an afferent volley will be produced.¹⁷ The transducer ion channels are nonselective cation or sodium channels that are gated not by voltage but by temperature, chemical ligands, and mechanical shearing forces.¹ Once they are activated, the channels open and sodium and calcium ions flow into the nociceptor peripheral terminal, producing an inward current that depolarizes the membrane.¹ When this depolarization is sufficiently large, it opens voltage-gated Na+ channels and triggers the generation of action potentials that are conducted to the trigeminal nucleus or the brainstem.¹⁸ Sensory neurons express several voltage-gated sodium channels that mediate conduction of the action potentials, including 2 that are unique to nociceptors: Nav1.8 and Nav1.9.¹Different ion channels that mediate orofacial and pulpal pain are Acid Sensing Ion Channel [ASIC3], tachykinin ion channels NK1, NK2, NK3, Transient Receptor Potential ion channels TREK1, TREK2, TRPV1, TRPV2, TRPV3, TRPV4 and TRPM3. These ion channels are concentrated in odontoblasts, capillary plexus and blood vessels in pulp, periodontal ligament and epithelial regions.^19,20,21 (Fig. 2)

Figure 2: Ion channels involved in pain¹

In teeth, 3 different theories are proposed which are involved in transmission of pain from the site of stimulus:^{19, 22, 4, 23} (Fig. 3)

Direct nerve stimulation theory(or) Neural theory

· Changes in tooth surface temperature are conducted through enamel, dentin and finally to sensory receptors located at DEJ causing neuron excitation.

Dentinal receptor theory (or) Odontoblastic transduction theory

· External stimulus is transmitted along odontoblasts and transferred to nerves via synaptic junctions between odontoblasts and nerves.

Hydrodynamic theory:

· It is the most accepted theory. It was proposed by Gysi, and later developed by Brannstrom et al. According to this theory, pain provoked by stimuli (thermal, chemical and mechanical) is a consequence of fluidal flow in the dentinal tubules, at the speed of 2-4 mm/sec. Such circulation stimulates the mechanoreceptors and leads to the initiation of neural impulses in subodontoblastic plexus of Raschkov and interodontoblastic plexus of Bradlow in the pulp. Stimuli cause either an inward (toward the pulp chamber) or outward (away from the pulp chamber) dentinal fluid flow in dentinal microtubules. Dentinal fluid flow-induced shear stress on intradental nerve terminals may activate mechano-sensitive ion channels and cause dental pain sensation.

Figure 3: Theories of dentin hypersensitivity in pain perception

Impulse conduction:

Impulses are carried from the dendrites down the axon by way of an action potential. The surface of the cell membrane is slightly negatively charged. An action potential begins with a sudden change from the normal resting negative potential to a positive membrane potential and then ends with an equally rapid change back to negative potential.¹³The electrochemical gradients for sodium, calcium, and chloride are more positive than the resting membrane potential in sensory neurons, the opening of ion channels permeable to these ions will cause the membrane potential to shift in the positive direction (depolarize).²⁴ Since the electrochemical gradient for potassium is more negative than resting potential, closure of active potassium channels not only depolarizes the membrane potential but amplifies current-induced voltage fluctuations due to the resulting increase in membrane resistance.²⁴ When the membrane becomes depolarized, there is a sudden permeability to sodium ions, allowing tremendous number of ions to flow into the interior of axon. The sodium channels begin to close and potassium channels open more than normally. Potassium diffuses to the exterior and reestablishes normal negative resting membrane potential by repolarization.¹³(Fig. 4)

Figure 4: Nerve conduction

Impulse conduction is faster in myelinated fibers than unmyelinated fibers because of the presence of saltatory conduction at the nodes of Ranvier along with the normal excitatory conduction.¹³

Synaptic transmission:¹³

Nerve signals are transmitted from one neuron to the next through interneuronal junctions called synapses. Each presynaptic terminal is separated from its adjacent neuron by a small distance called synaptic clefts. The synaptic vesicles are present in the presynaptic terminals, which contain transmitter substances when released into the synaptic cleft either excite or inhibit postsynaptic neuron. The postsynaptic neural membrane has both excitatory and inhibitory receptors.The mitochondria present in the presynaptic terminals provide the adenosine triphosphate required to synthesize new transmitter substances.The synaptic membrane of the presynaptic terminals contains large number of voltage-gated calcium channels. When the action potential depolarizes the terminal, large numbers of calcium ions, along with the sodium ions that cause most of the action potential, flow into the terminal. The quantity of transmitter substance that is released into the synaptic cleft is directly related to the number of calcium ions that enter the terminal.At the synapse, the membrane of the postsynaptic neuron contains large numbers of receptor proteins, which project out into the synaptic cleft as well as extend into the interior of the postsynaptic neuron. The portion that protrudes into the cleft acts as a binding area for the released neurotransmitters. The portion that extends into the neuron is the ionophore component and carries neurotransmitters into the neuron that can influence cell activity. (Fig.5)

Figure 5: Synaptic terminal

Pathways of pain:

Direct nociceptive activation is usually gone within minutes after withdrawal of the noxious stimulus, but the resulting pain often lasts much longer.²⁵ Fast type of pain is transmitted by A-delta fibers (myelinated) by Glutamate and slow type of pain is transmitted by C fibers (unmyelinated) by Substance P. The impulse is transmitted from periphery to subnucleus caudalis via first order neurons where they synapse with second order neurons in different laminae for fast and slow type of pain. They are then transmitted to different nuclei in thalamus region of brain via second order neurons which are then transmitted to the cerebral cortex to perceive it as pain via third order neurons.¹³

Figure 6: Pain Pathway

Nociceptive processing takes place within at least two distinct and parallel systems or tracts:^{12, 26} (Fig. 6)

· Medial pain system or Paleospinothalamic tract (for transmission of slow pain).

· Lateral pain system or Neospinothalamic tract (for transmission of fast pain).

Medial pain system composed of the insular cortex, anterior cingulate, and limbic structures is held responsible for processing emotional-affective and cognitive-behavioral components of pain. Lateral pain system is attributed to sensory-discriminative components of pain and includes the lateral spinothalamic tract, the ventral posterolateral nucleus of the thalamus, and somatosensory region.²⁷Impulses are relayed up the spinal cord and through the spinothalamic tract to output on the thalamus. In turn, the thalamus serves as the major “relay station” for sensory information to the cerebral cortex. Nociceptive pathways terminate in discrete subdivisions of thalamic nuclei known as the ventral posterior lateral nucleus and the ventromedial nucleus. From these nuclei, nociceptive information is relayed to various cortical and subcortical regions, including the amygdala, hypothalamus, periaqueductal grey, basal ganglia, and regions of cerebral cortex. Most notably, the insula and anterior cingulate cortex are consistently activated when nociceptors are stimulated by noxious stimuli, and activation in these brain regions is associated with the subjective experience of pain. In turn, these integrated thalamocortical and corticolimbic structures process somatosensory input and output neural impulses which influence nociception and pain perception.^{28, 29, 30}

Pathway of Fast pain: StimulusàA-delta fibers [first order neurons]àLaminae I of dorsal hornsàSecond order neuronsàThalamusà Reticular areas of brain stem + Ventral Posterior Lateral NucleusàSomatosensory Cortex

Pathway of Slow pain: StimulusàC fibers [first order neurons]àLaminae II, III of dorsal hornsàSecond order neurons àLaminave V of dorsal hornsàThalamusà Reticular nuclei of brain stem + Periaquiductal gray region + Tectal area of mesencephalon + Interlaminar & venterolateral nucleiàSomatosensory cortex

CONCLUSION:

The pulp is a tissue of high neural density. Most ofits sensory nerve terminals are distributed in the pulpdentin border zone and are thus in an ideal position torespond to external stimuli and to sense potential damage to the tooth. This literature review provides a compact information related to dental pain as necessary for the practitioner to understand and thereby provide the required medication.

REFERENCES:

1. Clifford J. Woolf. Pain: Moving from Symptom Control toward Mechanism-Specific Pharmacologic Management. Ann Intern Med.2004;140(6):441-451.

2. Massieh Moayedi, Karen D. Davis. Theories of pain: from specificity to gate control. J Neurophysiol. 2013;109(1):5–12.

3. Vignesh. R, Vishnu Rekha C, Parisa Norouzi Baghkomeh, Sankar Annamalai, D. Ditto Sharmin. Algesia and Analgesia in Pediatric Dentistry. Research J. Pharm. and Tech. 2019; 12(5):2559-2565.

4. Goranka Prpić-Mehičić and Nada Galić. Odontogenic pain. Medical Sciences 2010; 34:43-54.

5. Ofelia L. Elvir-Lazo, Paul F. White. The role of multimodal analgesia in pain management after ambulatory surgery. Curr Opin Anesthesiol. 2010 23(6):697–703.

6. Natalia E. Morone, Debra K. Weiner. Pain as the 5th vital sign: Exposing the vital need for pain education. Clin Ther. 2013;35(11):1728–1732.

7. Henry MA, Hargreaves KM. Peripheral mechanisms of odontogenic pain. Dent Clin North Am. 2007 Jan;51(1):19–44.

8. Coutaux A, Adam F, Willer J-C, Le Bars D. Hyperalgesia and allodynia: peripheral mechanisms. Joint Bone Spine. 2005;72(5):359-71

9. Hucho T, Levine JD. Signaling Pathways in Sensitization: Toward a Nociceptor Cell Biology. Neuron. 2007;55(3):365-76.

10. Sacerdote P, Levrini L. Peripheral mechanisms of dental pain: the role of substance P. Mediators Inflamm. Article ID 951920, 6 pages, 2012. https://doi.org/10.1155/2012/951920.

11. Arthur C. Guyton, John E. Hall. Textbook of Medical Physiology. Eleventh Edition. Elsevier Inc.; 2006: pg. no. 598-609.

12. Kim Barrett, Heddwen Brooks, Scott Boitano, Susan Barman. Ganong’s review of Medical Physiology. Twenty-third Edition; McGraw-Hill Companies, Inc.; 2010: pg. no. 167-171.

13. Jeffery P. Okeson. Bell’s Orofacial Pain. Fifth edition. Quintessence Publishing Co Inc.; 1995: pg. no. 100-110.

14. E.S. Troullos, R.D. Freeman, R.A. Dionne. The Scientific Basis for Analgesic Use in Dentistry. Anesth Prog. 1986;33(3):123–138.

15. Ashley PF, Parekh S, Moles DR, Anand P, Behbehani A. Preoperative analgesics for additional pain relief in children and adolescents having dental treatment. Cochrane Database Syst Rev.2012;9. Art. No.: CD008392. doi: 10.1002/14651858.CD008392.pub2.

16. National Pharmaceutical Council. Pain: Current understanding of assessment management and treatments. www.americanpainsociety. org/uploads/pdfs/npc/section_1.pdf. (seen on 12.10.2014)

17. Jonathan Brooks, Irene Tracey. From nociception to pain perception: imaging the spinal and supraspinal pathways. J. Anat. 2005;207(1):19–33.

18. Hans-Georg Schaible, Andrea Ebersberger, Gabriel Natura. Update on peripheral mechanisms of pain: beyond prostaglandins and cytokines. Arthritis Res Ther. 2011;13(2):210.

19. Min Lin, Zheng Yuan Luo, Bo Feng Bai, Feng Xu, Tian Jian Lu. Fluid Mechanics in Dentinal Microtubules Provides Mechanistic Insights into the Difference between Hot and Cold Dental Pain. PLoS ONE. 2011;6(3):e1806-8.

20. Niharika Jain, Abhishek Gupta, Meena N. An Insight Into Neurophysiology of Pulpal Pain: Facts and Hypotheses. Korean J Pain. 2013;26(4):347-355.

21. Paola Sacerdote, Luca Levrini. Peripheral Mechanisms of Dental Pain: The Role of Substance P. Mediators Inflamm. 2012, Article ID 951920.

22. G. S. Kumar. Orban's Oral Histology and Embryology. Thirteenth Edition. Elsevier Inc.; 2011: pg. no. 120-129.

23. Antonio Nanci. Ten Cate’s oral histology: development, structure and function. Eighth Edition. Elsevier publications; 2012: pg. no. 198-201.

24. Adrienne E. Dubin, Ardem Patapoutian. Nociceptors: the sensors of the pain pathway. J Clin Invest. 2010;120(11):3760-3772.

25. Cliff K. S. Ong, R. A. Seymour. Pathogenesis of Postoperative Oral Surgical Pain. Anesth Prog. 2003;50(1):5-17.

26. Yu-Feng Xie, Fu-Quan Huo, Jing-Shi Tang. Cerebral cortex modulation of pain. Acta Pharmacol Sin. 2009;30(1):31–41.

27. Mike Brügger, Dominik A. Ettlin, Michael Meier, Thierry Keller, Roger Luechinger, Ashley Barlow, Sandro Palla, Lutz Jäncke, Kai Lutz. Taking sides with pain – lateralization aspects related to cerebral processing of dental pain. Front Hum Neurosci. 2011;5(12):1-13.

28. Eric L. Garland. Pain Processing in the Human Nervous System: A Selective Review of Nociceptive and Biobehavioral Pathways. Prim Care. 2012;39(3):561–571.

29. Vignesh. R, Vishnu Rekha C., Parisa Norouzi Baghkomeh, Sankar Annamalai, D. Ditto Sharmin. Algesia and Analgesia in Pediatric Dentistry. Research J. Pharm. and Tech. 2019; 12(5):2559-2565.

30. Trophimus Gnanabagyan Jayakaran, Vignesh R, Shankar P. Local Anesthetics in Pediatric Dental Practice. Research J. Pharm. and Tech 2019; 12(8): 4066-4070

Received on 07.01.2020 Modified on 10.03.2020

Research J. Pharm. and Tech. 2021; 14(1):482-486.

DOI: 10.5958/0974-360X.2021.00088.3