The understanding of the inflammatory, pain and healing processes is of great importance in the practice of dentistry. While bacterial byproducts or immunological agents arising from host inflammatory cells play a major role in pulpal pathosis, the release of neuropeptides from peripheral sensory nerve endings has also been suggested to contribute to pulpal inflammation and pain. The latter process has been termed neurogenic inflammation and has been suggested as an important component in the development of early periapical lesions. Pulpal pain has been widely researched yet there are a number of pain conditions not well understood. Examples are: 1) Symptomatic pulpitis, 2) Post-extirpation pain, 3) Individual variability of dental pain, and 4) Difficulty anesthetizing acutely inflamed pulp. This article reviews the current literature with more focus on neurogenic inflammation in an attempt to offer newer and clearer explanations for pulpal pain conditions.
 

Dental nerve fibers are mainly sensory, but some sympathetic fibers have also been found along blood vessels in the central pulp. Most of the sensory nerve fibers pass through the apical foramen and then branch extensively in the coronal region before terminating in the peripheral pulp. An interesting and consistent finding is the extension of many nerve terminals into coronal dentin. The sensory nerve fibers in the dental pulp originate in the trigeminal ganglion and are categorized, from smallest to largest diameter, into C-fibers, A-delta and some A-beta fibers. On the other hand, post- ganglionic sympathetic nerve fibers originate in the superior cervical ganglion. A-delta fibers are myelinated low-threshold mechanico- receptors and are responsible for the so-called "first pain signal". C-fibers are unmyelinated, high-threshold fibers. They are termed poly- modal because they respond to several types of stimuli such as mechanical, chemical, or thermal stimulation of the pulp. C-fibers most likely mediate the sensation of "second pain."

For years, sensory nerve fibers were thought of as static structures producing pain upon activation and stimulation by the inflammatory mediators. This is not the whole picture. Recent neurophysiological studies have shown that sensitized nerve fibers release neuropeptides (NP), which in turn modulate the inflammatory process. This has been termed neurogenic inflammation. Sensitized nerve fibers also produce pain of special charac- teristics; a perceptual state termed hyper- algesia.¹ More interestingly, peripheral sensory nerve fibers show sprouting (branching) in the inflamed areas.² This sprouting is reversible and disappears as the inflammation subsides. The CNS is also not a static structure and seems to react to the continuous flow of pain impulses.³ The phenomenon is termed central sensi- tization.

These four processes: neurogenic inflamma- tion, nerve sprouting, hyperalgesia and central sensitization will be reviewed in this paper. The literature is purposefully reviewed to offer explanations for a number of pain conditions that are not well understood.

Neurogenic Inflammation

Neuropeptides (NPs) are proteins synthesized in the cell body of the primary afferent nerve fibers, and then transported both to CNS and to the peripheral nerve endings.⁴ In the dental pulp, NPs are transported from the cell body in the trigeminal ganglion via the axons to the nerve endings and stored in vesicles. During pulpal inflammation, the peripheral infla- mmatory mediators stimulate and sensitize the sensory nerve fibers (nociceptors) to release the stored NPs. From a biologic point of view, most important NPs are calcitonin gene-related peptide (CGRP),⁵ substance P (SP),⁶ and neuro- kinin A (NKA).⁷

Pulpal sympathetic nerves release different class of neuropeptides such as neuropeptide Y (NPY).⁸'⁹ Vasoactive intestinal peptide (VIP) is another neuropeptide detected exclusively in parasympathetic neurons. Interestingly, VIP persists in the pulp even after injuring the inferior alveolar nerve and sympathectomy.¹⁰ Thus, it has been suggested that para- sympathetic innervation does exist in pulp. Pulpal parasympathetic innervation has been a controversial issue. However, the neuro- physiological investigations provided better classification of pulpal innervation than that of the histological studies.

As early as 1968, Kroeger found that when the inferior alveolar nerve was stimulated, the intrapulpal pressure increased.¹¹ The same finding was observed in dogs and rat's teeth following nerve stimulation.⁶ More specific studies showed that these changes were due to NP release.

Neuropeptides produce multiple biological effects and appear to have both circulatory and immuno-modulation modes of actions, injec- tion of SP intradermally in rats produced plasma extravasation.¹² SP releases histamine from mast cells,⁶ which in turn stimulates the release of SP.¹³ Pre-treatment with anti-histamines reduces SP-induced extravasation.¹⁴ Thus, it has been suggested that SP-induced extravasation and edema is histamine-dependent.¹⁵ Edema induced by histamine and bradykinin is potentiated by CGRP and inhibited by pretreatment with anti-CGRP.¹⁶ This is because CGRP potentiates SP-induced extravasation through inhibition of SP degradation.¹⁷ Injection of CGRP in man induces a potent long- standing vascular response.¹⁸ Also, systemic administration of CGRP caused marked lowering of blood pressure in rats,⁴ hypotension and tachycardia in man.¹⁹ Consequently, CGRP is considered among the most potent endogenous vasodilators.

Local application of bradykinin in deep dentinal cavities in cats significantly increased pulpal blood flow in innervated but not denervated teeth.²⁰ This indicates that bradykinin is dependent as a vasodilator on NP. Plasma extravasation produced by SP, and vasodilatation produced by CGRP are integral components of the inflammatory reaction. It provides the area with plasma-borne precursors for the inflammatory mediators such as arachidonic acid and kininogen. Tissue enzymes convert an arachidonic acid to leukotriens and prostaglan-dins, and kininogen to bradykinin. The resulting inflammatory mediators will sensitize the nerve ending and the cycle goes on. Hargreaves et al proposed that CGRP and SP actions potentiate the vascular response and maintain the inflammatory reaction through a local positive feedback mechanism.²¹

By definition, neurogenic inflammation is the inflammatory response mediated by neuropeptides, which are released from stimulated peripheral nociceptors.

Peripheral Nerve Sprouting

CGRP-containing nerve fibers in the pulp are considered a major component of dental innervation.²² Therefore, the responses of these fibers have been studied extensively using different experimental injuries such as cavity preparation, pulpal exposures, occlusal trauma and replantation. Most of the fibers survive these injuries and continue to innervate dentin were found only in tubules occupied by viable odontoblasts. Dentinal cavities in rat molars caused depletion of CGRP and SP. However, by 1-2 days, those fibers have greater neuropeptide immunoreactivity than normal and have began extensive sprouting reaction. Nerve sprouting eventually subsided when inflammation was reduced and when reparative dentin has covered the injury site.²³ Following tooth injury, Byers found that nerve growth factor synthesis proceeds the increased CGRP and SP nerve sprouting.²⁴ The author suggested that nerve sprouting is a vehicle to bring more neuropeptides to the inflamed area. Similar findings of nerve sprouting and increased levels of CGRP were also detected following tooth extraction,²⁵ induced occlusal trauma,²⁶ experi- mental replantation²⁷ and orthodontic tooth movement.²⁸

Pulpal exposures in rat molars produced pulpal CGRP nerve fiber sprouting along the abscess borders,² and two-fold increase in pulpal level of SP and CGRP with peak levels observed 7-14 days after the exposure.²⁹ Pulpal exposures also produced periapical nerve sprouting 5 days after the pulpal injury and persisted at later stages, with strong positive staining. Based on these results, it has been theorized that the ensuing neurogenic inflammation with the resultant release of NPs and apical nerve sprouting is responsible for the early appearance of the apical lesion.²

Hyperalgesia

Pain produced by inflammation produces a perception that is distinctly different from pain induced by transient non-inflammatory stimuli such as needle insertion. Inflammation causes electrophysiologic changes in the peripheral nociceptors responses to produce a perceptual state of hyperalgesia. It results in a great dentinal responsiveness to stimuli such as heat, cold, and mechanical stimulation. Willis¹ defined hyperalgesia as the perceptual state which is characterized by spontaneous pain, decreased pain threshold, and an increased magnitude of perceived pain for a given stimulus.

Central Sensitization

Peripherally induced inflammation in experimental animals produces a number of central neural changes. These include increase in the CGRP-positive cells within L4 dorsal ganglion,³⁰ increased levels of SP and CGRP in the spinal cord,³¹ enhanced spontaneous firing,³² increased discharge response,³³ and expanded receptive fields in dorsal horn neurons.³⁴ Moreover, when injected intrathecally, CGRP altered the nociceptor behavior in mice.³⁵ Taken together, these findings suggest that the enhanced release of CGRP and SP in the dorsal horn may serve as a biochemical marker for the development of hyperalgesia.³ This hyperexcitability of the dorsal neurons at the level of spinal cord is termed central sensitization and is attributed, as a major mechanism, to produce hyperalgesia.³² Central hyperalgesia may contribute to acute as well as chronic pain states, and therefore, the CNS is no longer viewed as a static monolith that does not respond to peripheral nociceptive input.

Pulpal pain has been widely researched, yet there are a number of pain conditions not well understood. Examples are: 1) Symptomatic pulpitis, 2) Post-extirpation pain, 3) Individual variability of dental pain, and 4) Difficulty anesthetizing acutely inflamed pulp. Putting in mind the literature reviewed earlier, a discussion will be made here in an attempt to provide further explanations to these clinical pain conditions.

Symptomatic Pulpitis

Symptomatic pulpitis is also known as acute irreversible pulpitis or acute pulpalgia. The presence of hyperalgesia. It has been proposed that "hyperalgesic pulpitis" is a more accurate clinical term to describe the neurophysiology status of the inflamed pulp.²² Understanding signs of hyperalgesia offers a physiologic rationale for many of the symptoms of acute pulpitis. Spontaneous pain is produced by the spontaneous activity of the sensitized nerve endings. It is possible to speculate that the lingering pain following vitality testing is due, in part, to the local positive feedback cycle produced by secreted NPs. Central sensitization may as well contribute to the perception of such prolonged pain sensation. Nahri³⁶ suggested that throbbing pain may be due to the mechanical threshold reduced to the extent that arterial pressure wave of a heart beat is sufficient to activate sensitized pulpal nerve fibers.

Post-extirpation Pain

Effective extirpation of acutely inflamed pulps does not always relieve patient symptoms completely. Central sensitization causes neural changes that may persist even after removal of inflamed pulpal tissues similar to phantom limb pain. Thus, it is possible that dental pain remains even when no peripheral (pulpal) input can be detected. Another explanation for post- extirpation pain is the presence of the early periapical nerve sprouting and inflammation that accompanies acute pulpitis. Such periapical inflammation is often noticed as widening of the periodontal ligament space, but sometimes is hard to detect radiographically. This reversible periapical sprouting will eventually disappear few days after the extirpation. It is not surprising then to recommend the prescription of mild-to- moderate analgesics following pulpal extirpation.

Individual Variability of Dental Pain

It appears that the vasodilatation and edema formation produced by sensory NPs is counteracted by vasoconstriction produced by the release of sympathetic NPs such as NPY. Like most of the sympathetic innervation, pulpal NPY- containing fibers are associated with blood vessels. Thus, it has been suggested that while sensory NPs potentiate inflammation through vasodilatation, sympathetic NPs represent an endogenous mechanism to control inflammation
control mechanisms is variable. Olgart etal³² attributed this variability to explain why symptoms of pain, and probably pain thresholds, are so unpredictable and individual.

Difficulty Anesthetizing A cutely Inflamed Pulp

Establishing a profound anesthesia for an acutely inflamed tooth is sometimes a serious clinical challenge to the dentist. This is true whether the planned procedure is pulpectomy or tooth extraction. Two theories are widely accepted as possible explanations. The first theory states that the acidic pH of the inflamed area inhibits the dissociation of the local anesthetic, while the second theory stresses that the edematous inflamed tissues cause rapid transportation of the local anesthetic. In either case, failure to produce profound anesthesia will result.³⁸ These explanations sound logical when the local anesthetic is administered locally as in infiltration injections. However, it does not address the problem when the local anesthetic is administered in remote sites such as block injections. Research in the field of neuro- physiology has offered a new explanation for the ill understood situation. Pulpal inflam- mation causes pulpal and periapical nerve sprouting,²²⁴ increased NPs staining in axonal nerves,² increased neuropeptide levels in trigeminal ganglion,³⁰ and CNS.³²-³⁷ Collectively, it has been suggested that these neural plas- ticity and cytochemical changes extending throughout the affected nerve fibers alter the nerve capacity for anesthesia.

The results of current pharmacological studies have shown that a number of drugs inhibit NPs release. For example, Lidocaine 2% blocks the evoked-release of CGRP from dental pulp.³⁰ Interestingly, adrenergic agents, such as epinephrine and norepinephrine, have potent actions for inhibiting the release of CGRP.⁴⁰ This hints to the possibility that the enhanced efficacy observed with the vasoconstrictor- containing local anesthetic drug may be due to not only vasoconstriction but also to an inhibitory action of adrenergic agonists on certain primary afferent fibers.
 

Pain represents a major stimulus for patients who seek emergency dental treatment. On the other hand, fear of pain represents a significant barrier that discourages patients from seeking routine dental care. Research conducted in the last 20 years has probed our understanding of pulpal pain. Following the scientific attitude, we are obligated to reevaluate our classical assumptions and explanations of pain mecha- nisms and pain management. Better under- standing of pulpal pain mechanism enables the clinician to diagnose and manage acute pain conditions effectively, thus, reducing public dental phobia.

Regulation of peripheral NPs release may provide a new therapeutic approach for managing pain and inflammation that accompanies injuries to the pulp and periapex. Future research is promising in providing drugs that inhibit NP. These drugs may be used in endodontic emergencies in the form of pulp capping agents, intracanal medicaments, infiltration injections, or incorporation with local anesthetics.

Despite the large body of literature of the pulpal neurophysiology, it is surprising to note that what is taught in the undergraduate dental programs is quite little. Academicians are urged to incorporate the new pain theories that challenge the known ones in the didactic courses.