Pain may also appear in the mouth, face (neuralgia and stinging or tingling in the cheeks or tongue), and teeth (sometimes simulating dental decay with involvement of the pulp).

The mouth and teeth may become the focus of obsessive attention also due to the actual existence of frequent occlusion-related disorders (“bad bite”), which due to over-sensitivity (hyperalgesia/hyperesthesia) and “over-attention” to the orofacial region (hypervigilance), may become cause preclinical conditions to become symptomatic.

A great deal of clinical and experimental research has gone into investigating the peripheral receptors (fibers and corpuscles responsible for registering pain) and the modulation circuits of the central nervous system (cortex and thalamus) involved in the perception of mild and intense pain; since the results have not always been shared by the scientific community at large, the issue is replete with conflicting assumptions.

For many years Melzack and Wall’s gate control theory has dominated the scene: through a “gate” activated by non-painful impulses (i.e. deep tactile, vibrations) at the periphery, and the “facilitating” or “inhibiting” action of influences coming from the “higher” parts of the central nervous system like the cerebral cortex, a “gate” mechanism stops the entry and progress of the pain signal at the first “station” in the pathway towards the center (the “higher” message receiving and processing centers of the brain).

This mechanism is believed to take place at the connection between the nerve ending and the bone marrow, i.e. the nerve bundle running longitudinally along the spinal cord that encloses nerves which, at different levels, enter and exit it on their way to the higher centers located in the brain.

This theory has prevailed for decades, supplying a convincing explanation for the way cognitive conditions (thoughts and feelings) and emotional affective conditions (moods and emotions) condition pain perception.

It also explains how treatments aimed at the peripheral nervous system (acupuncture, acupressure, electro-stimulation, etc.) can influence our perception of a stimulus, transmitting non-painful “deeper” (proprioceptive) messages.

Therefore, stimuli may or may not be perceived as painful depending on the activity of the gate and the central or peripheral influences controlling it.

The brain (thalamus, hypothalamus and cortex) and the functionally more advanced structures on the one hand and the peripheral tissues on the other, seem to be involved in quantifying painful sensations as a result of the activity of the systems described above.

But this theory fails to adequately explain many situations where changes in the “pain threshold” (i.e. the minimum stimulus producing pain) seem to be affected by factors not controlled by these central and peripheral influences (e.g. endogenous chemical modulators, hormones, etc.).

Barry Sessle, an Australian researcher who is currently the director of the Toronto University pain research center and a former dean of the faculty of dentistry of the same university, besides being a well known international expert in orofacial pain, has recently drawn attention to the mechanism through which peripheral sensitization of the pain receptor occurs at the peripheral level (i.e. the tissue in which an injury takes place, such as the maxillary bone in which a tooth abscess develops) (Sessle B.J., ICOT 2005, International Conference of TMD: The Scientific Basis of Orofacial Pain: Clinical Decision Making: Sydney, August 26-28, 2005: Sessle, B.J. Trigeminal Central Sensitization, Analgesia, 2005, in press.)
This could be because of the direct action of chemicals produced by trauma, and the inflammatory process acting at the periphery on sensory organs (pain receptors– nociceptors – in the free form - A delta or C fibers - and Pacini corpuscles etc). These substances are called

bradykinin, prostaglandins, cytokines, etc. However, other chemicals that normally regulate many brain functions (active amino acids, opioids, etc.) may also be involved.

All these substances seem to act by modifying the excitability of the pain-sensitive structures (nociceptors), generally with an enhancing effect.

This phenomenon, called “hyperalgesia” presents with heightened sensitivity to pain, or “allodynia”, leading to the paradoxical phenomenon of a generally painless stimulus (light touch, drafts or a slight breeze, rubbing of clothing) being perceived as painful.

The pain impulse then travels to the brainstem (intermediate station on the journey of the “pain signal” towards the thalamus and cortex), then directly or indirectly through more complex collateral pathways, (the amigdala and locus ceruleus/LC), where it is “labeled” as “threatening”, or a source of danger to the body, which thus learns to recognize it in the emotional sphere.

This acquired ability to identify and recognize painful experiences also enables us to develop avoidance and defense strategies (fight or flight – see chapter on Anxiety).

In the brainstem, the impulse stimulates a series of nerve cells (nerve stations located between the pathways directed towards the center) that, when activated, produce inhibiting effects (descending inhibitory influences), and when inhibited allow the pain impulse to enter and travel towards the brain, the final pain perception and cognition center.

The result of these partly conflicting influences is a generally greater proneness to allowing impulses to pass through that are encoded as painful.

This phenomenon, generated by the higher centers, is called “central sensitization”.

According to Sessle, central sensitization can last for hours or days, depending on the type of injury or lesion; at the lesion site it permits the triggering of the phenomena described for peripheral sensitization, i.e. hyperalgesia, or enhanced sensitivity, and allodynia, or painful perception of normal stimuli.

Numerous substances have been described at the Central Nervous System (CNS) level that are involved in this “central” pain enhancement process, attributing to this phenomenon a more general neuroplastic susceptibility (adaptive dynamics) typical of the CNS (Levi Montalcini, 1980), in particular, NMDA, neurokinins, purinergic receptors, opioids, GABA, 5HT (Sessle, 2005).

This “fluctuation” in the level of sensitivity to stimuli, and thus variability in perception as a painful event, explains why the functional architectures involved in pain phenomenology (pain physiology) are not rigid and unchanging functional structures, but are rather subject to multiple intrinsic and extrinsic environmental influences, including those of the body itself.

Extrinsic factors may be drugs, physical treatments and physiotherapy.

Drugs have the advantage of working both on peripheral pain modulation, at the receptor level, and along the pathways towards the brain. However, many drugs obviously also have adverse side effects.

Recent findings have also proven that the administration of inactive drugs (placebo) can be paradoxically effective in a significant percentage of case, since the mere “awareness” of taking them activates the same neuronal receptors as those for active drugs.

Similarly, significant influences on pain perception can be caused by intrinsic mental factors (emotional and affective disorders) like stress, anxiety, and depression that may be psychobiological (hormonal psychoneuroendocrine influences within the same limbic system involving the hypothalamus and pituitary gland) or hormonal, neuro-hormonal and biological, involving the target glands or tissues and organs with endocrine functions (production of endogenous opioids, cortisol, growth hormone (GH) ghrelin, melatonin, prolactin, etc.).

Disciplines like chronobiology and practices like chronotherapy (wake and light therapy, Wirz Justice, 2004; Benedetti et al., 2004: ISAD Cancun), open up significant prospects for interpreting and treating chronic pain related to depression and other mood disorders that do not respond to conventional approaches (ultradian, estral, menstrual and circadian rhythms etc.).

The onset of central and peripheral sensitization with or without ongoing peripheral tissue injury (primary nociceptive pain) might contribute to the onset of the “pain entity” that we define as “chronic pain”.

In such a condition, automatic mechanisms like defense, alarm, reaction to stimuli and pure emotional states like anxiety and fear aroused by pain perception, which may be useful in acute painful states, escape the control of the “pain system” (pain physiology) and give rise to a self-maintaining and self-perpetuating state, ending up in a real pain vicious circle (pathophisiology of chronic or persistent pain) (Cousins, M.: Persistent Pain, a disease entity. The Scientific Basis of Orofacial Pain: Clinical Decision Making: Sydney, August 26-28, 2005; Siddal P.J. Cousins: Persistent Pains a disease entity: implications for clinical management; Anest. Analg, 2004: 99, 510-520).

The multifactorial aspect of the phenomenon justifies the complexity of its foreseeable clinical management. This explains the sometimes surprising success of many non-conventional treatments rejected by advocates of evidence-based-medicine.

Local factors (i.e. intensity of the stimulus, severity of the tissue injury, structural and functional integrity of the pain sensors/receptors), and central nervous and hormonal factors, (i.e. central nervous system centers and circuits, psychoneuroendocrine axes), are believed to act in the medium and long term in the structuring of the pain entity, generating situations that clinicians label as chronic musculoskeletal pain, orofacial pain, neuralgias and headache.

As regards the latter, it is particularly interesting to note that current imaging-based diagnostic methods (based on the traditional concept of radiology) such as PET (Positron Emitting Computer Tomography) and latest generation functional NMR (Nuclear Magnetic Resonance) have highlighted the existence of “neurobiological” processes rather than the vascular processes that were once believed to be involved (i.e. anatomo-functional changes in specific cerebral structures rather than the vasodilatation of several cerebral arteries).

Both episodic and chronic headache, with more than fifteen attacks per month, may be caused by a dysfunction or “dysregulation” of the brainstem (the portion of the brain lying below the cortex). In particular, hyperactivity (hyperfunction) of the pons (the lateral and posterior part of the brainstem) associated with de-activation of the half corresponding to the side of the head not affected by so-called migraine headaches (headache on one side of the head)(Goadsby, P.: The neurobiological basis of migraine/cluster headache: update on treatment; The scientific basis of clinical decision making, Proceedings of the ICOT Meeting, Sydney 2005)

It is worth noting that several researchers have also suggested the existence of a “third pathway” of pain modulation, acting synergically to the peripheral and central pathways (in the lesion site and in the intermediate nerve stations including the brain, respectively).

It is believed that this mechanism consists in the direct influence of neuroactive substances (endogenous opioids and autonomous, ortho- and parasympathetic nervous system) on several types of pain receptors (e.g. Pacini corpuscles).

Santini, who first formulated these hypotheses, called this phenomenon “sympathetic/parasympathetic sensory coupling”, which means the functional coupling of the sympathetic/parasympathetic system at the peripheral receptor level.

Based on this theory, which though thought-provoking, has not yet been proven, it might be possible to convincingly explain the influence that emotional states can have directly at the entry of the stimulus, countering the classic gate theory of Melzack and Wall.
The “ortho-sympathetic” and “parasympathetic” parts of the autonomic nervous system are those involved in the acute phases of stress, and are constantly on alert and ready to act during anxiety attacks or depressive anxiety states.

Clearly, in light of these assumptions, many of which are already backed by substantial scientific evidence, clinical problems such as “back ache” and “neck pain”, toothache, painful jaws, temporomandibular joint pain and earache, as well as neuralgias and headache, could in future be framed in a different diagnostic perspective.

Special attention should be given to the psychological aspects of pain, but these too ought to be reconsidered from the psychobiological, and therefore neurochemical standpoint.

The clinical therapeutic consequences might be spectacular, since treatment could be aimed towards restoring a more favorable neurohumoral status when chronic pain (somatic, orofacial or visceral) is the symptomatic expression of a more generalized neuroendocrine dysregulation (especially of the circadian biorhythm). This could generate a disorder currently defined as seasonal anxiety depressive disorder and, for some, perhaps also forms of endogenous depression (Seasonal Affective Disorders/SAD and Non-Seasonal Affective Disorders/NSD).

These activities seem to be effective because they stimulate the nervous system at several levels and in numerous ways. In some cases the result is real stress. Therefore physiological responses are triggered that promote a rapid “resetting” of the neuro-hormonal axes (hypothalamus-pituitary-adrenal and hypothalamus-pituitary-thyroid), and also rebalance the biorhythms of hormones like melatonin (the most widely researched), ghrelin, growth hormone (GH) and prolactin, which are involved in the modulation of over thirty endocrine sub-functions.
Obviously there is still a long way to go before these and perhaps other treatments are validated and standardized. However, it is undeniable that there is an exciting new chapter opening in the pathophisiologic interpretation of the causes of many diseases, including those related to stress, such as anxiety and depression, the latter being destined to become the greatest threat to human wellbeing after 2020 (WHO Report, Scientific American, September 2005).

Fascinating prospects are already opening up in the treatment of patients who cannot tolerate or refuse the traditional protocols currently employed in the treatment of this devastating illness.
(Wirz-Justice. A.: WHO Report, ISAD Proceedings, Cancun 2004).