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”.^2,3 Pain 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.

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.⁵ James 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.^7,8,9

Since 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 neurobiology 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 pain chemistry”, “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 neurochemistry of dental pain were selected. The necessary data from results of the selected studies were also taken into consideration.

A etiology 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:

ü Orofacial pain can be classified as:

o Somatic

· Superficial [Skin and Mucous Membrane]

· Deep

o Musculoskeletal [Periodontium] and Visceral [Pulp]

o Neuropathic

ü Based on duration, pain can be classified as:

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

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

ü Based on nature, pain can be classified as:

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

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

ü Based on site, pain can be classified as:

o Primary - Pain at the site of stimulus

o 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)

Neurochemistry:

Pain is mediated by the function of numerous intra- and extra-cellular molecular messengers involved in signal transduction in the peripheral and central nervous systems.^{4, 14} All nociceptors, when activated by the requisite mechanical, thermal, or chemical stimulus, they transmit information.¹⁵ Sensitized nociceptors have spontaneous activity, a decreased threshold, and prolonged responses to suprathreshold stimuli. In addition any inflammatory process is a complex series of biochemical and cellular events involving a variety of inflammatory mediators and algogenic substances¹⁶ are secreted at site of the original injury to stimulate nociceptors.¹⁵Some of these factors act directly on the nociceptor terminal to activate it and produce pain (nociceptor activators), and others sensitize the terminal so that it becomes hypersensitive to subsequent stimuli (nociceptor sensitizers).¹⁷

The neural effects of these algogenic substances involve either activating or sensitizing nociceptors¹⁶and result in the production of second messengers and the downstream activation of protein kinase and phospholipases. The second messengers regulate the activity of the many receptors and ion channels which open initiating and propagating action potentials in the sensory neurons¹⁴and increase neuronal excitability, resulting in enhanced neuronal firing¹⁸ leading to the transmission of afferent signals to the dorsal horn of the spinal cord or subnucleus caudalis¹⁵ and thus relate to pain. (Fig. 1)

Figure 1: Neurochemistry in pain

There are at least 3 sources of algogenic substances and neurotransmitters:¹⁶

ü Damaged cells themselves,

ü Secondary to plasma extravasation and lymphocyte migration, or

ü Nociceptor itself

· The nociceptors themselves can release substances that enhance nociception.

Neurotransmitters:¹⁶

I. Potassium:

Elevated extracellular potassium caused by its release from cytosol depolarizes neurons by changing the potassium electrochemical driving force for current through potassium channels open at the resting potential. An increase in potassium will excite all neurons as well as nociceptors.

II. Adenosine Tri Phosphate:

Adenosine Tri Phosphate was shown to open nonspecific cation channels on sensory neurons, thus forming a direct connection between ATP release during tissue damage and excitation of sensory neurons.

III. Bradykinin:

Bradykinin is synthesized in plasma whenever blood vessels are damaged because it is a by-product of the cascade triggered by activation of the coagulation system. The enzyme prekallikrein is converted to kallikrien, which then acts on the bradykinin precursor kininogen, resulting in the release of bradykinin into the tissues. Bradykinin is a potent activator of nociceptors. Bradikinin binds to B₂ receptors on sensory neurons and results in the stimulation of phospholipase C pathway with the activation of the protein kinase C cascade that has been demonstrated to stimulate substance P secretion from sensory endings.¹⁴

IV. Prostaglandin:

Prostaglandins are metabolized from arachidonic acid from damaged cell walls. The events following tissue damage involve breakdown of the phospholipids of the cell wall to arachidonic acid mediated by the enzyme phospholipase A₂. Arachidonic acid is further converted to prostaglandins by the enzyme Cyclo-oxygenase. Prostaglandin E₂ has no direct pain-producing activity, but it does sensitize receptors on afferent nerve endings to the actions of bradykinin and histamine.¹⁶ It acts on G-protein-coupled prostaglandin E receptors that increase cAMP. This activates protein kinase A, which finally leads to a phosphorylation of transient receptor potential V₁ receptors and voltage-gated Na+ currents leading to stimulation of an impulse.¹⁹

V. Serotonin:¹⁶

Serotonin can be released from activated platelets and from mast cells. Serotonin is able to activate nociceptors and potentiate the effect of other inflammatory mediators such as bradykinin.

VI. Substance P:^{14, 16, 20, 15}

Substance P is a neuropeptide synthesized in the body of the nerve cell of the A-delta and C-fibers, both bipolar neurons with the cell body situated in the spinal ganglion of the dorsal root. It is highly concentrated in peripheral tissue such as dental pulp around blood vessels and associated with odontoblasts which modulate inflammation by altering the release of histamine and prostaglandins. Substance P induce vasodilation, leak proteins and fluids into the extracellular space near the terminal end of the nociceptor, and stimulate immune cells which contribute to the inflammatory soup. As a result of these neurochemical changes in the local environment of nociceptors, the activation of Aδ and C fibers increases, and peripheral sensitization occurs. Substance P primarily acts on neurokinin receptors and simulation of the neurokinin1 receptor induces several second messengers systems, such as phospholipase C intracellular inositol 1,4,5-trisphophate turnover with subsequent elevation of intracellular calcium. It results in neurogenic inflammation of the dental pulp by causing vasodilatation and endothelial cell contraction with increased blood vessel permeability, which allows plasma extravasation and mastocyte degranulation. The mastocyte granules release histamine, which in turn further amplifies vascular processes and activates nociceptors.

VII. Norepinephrine:

Adrenal medulla is an important source of noradrenaline production and that the pulp has receptors for these compounds located mainly in the membranes of blood vessels and some nerves.²¹ Nociceptive signal transduction up the spinothalamic tract results in elevated release of norepinephrine from the locus coeruleus neurons projecting to thalamus, which in turn relays nociceptive information to somatosensory cortex, hypothalamus, and hippocampus.

VIII. Endorphins:

Opioid receptors in neurons of the dorsal horn of the spine and the periaqueductal grey in the brain result in inhibition of pain processing and analgesia when stimulated by opiates or endogenous opioids like endorphin, enkephalin, or dynorphin.¹⁵ Among the final actions of the activated receptor, the release of endorphins from immune cells increases the peripheral antinociception. Endorphins produce a decrease in nociception. Endogenous opioid peptides, which are present in large quantities in the brain (subnucleus caudalis and the substantia gelatinosa of the spinal cord) are naturally occurring, pain-suppressing neurotransmitters and neuromodulators. They reduce pain transmission by preventing the release of the excitatory neurotransmitter substance P from the primary afferent nerve terminal.²¹

IX. Nerve Growth Factor:

Peripheral nerve injury results in nerve growth factor release from Schwann cells and fibroblasts in the area of the injury. Binding of nerve growth factor to the Tyrosine kinase A receptor on primary afferent nociceptors forms Nerve growth factor / Tyrosine kinase A complex that is internalized and transported to the neuron cell body resulting in phosphorylation of the transient receptor potential ion-V₁ channel and rapid sensitization of nociceptors to heat. Nerve growth factor binding to Tyrosine kinase A produces a rapid facilitation of sodium currents and suppresses outward potassium currents, resulting in increases nociceptor activity.¹⁸

X. Glutamate:¹³

It is an amino acid secreted by presynaptic terminals in many of the sensory pathways and areas of cortex resulting in excitation of nociceptors.

XI. Acetylcholine:¹³

It is secreted by neurons in many areas of brain but specifically by motor cortex, basal ganglia and by motor neurons that innervate skeletal muscles having an excitatory effect on nociceptors.

XII. Others:^{13, 16, 15, 3, 22}

· Leukotriene B4 lowers the firing threshold of pain fibers and thus stimulates nociceptors directly.

· Gama - Amino Butyric Acid is also involved in the central modulation of pain processing, by augmenting descending inhibition of spinal nociceptive neurons.

· Histamine is released by mast cells during inflammation activates nociceptors.

CONCLUSION:

The pulp is a tissue of high neural density. Most of its sensory nerve terminals are distributed in the pulp dentin border zone and are thus in an ideal position to respond 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.

REFERENCE:

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

15. 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.

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

17. Mark Donaldson, Jason H. Goodchild. Appropriate analgesic prescribing for the general dentist. Gen Dent. 2010;58(4):291-7.

18. Michael H. Ossipov. The Perception and Endogenous Modulation of Pain. Scientifica. 2012, Article ID 561761.

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

20. David B. Goodalet. The Role of Substance P in simultaneously mediating oral pain and inflammation. Anesth Prog. 1981;28(2):41–43.

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

22. 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 26.03.2020

Research J. Pharm. and Tech. 2020; 13(11):5631-5634.

DOI: 10.5958/0974-360X.2020.00981.6