Abstract Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. For more than a century, views on the nature of pain sensation have been dominated by three major theories – the Specificity theory by Frey, the Intensivity theory by Goldscheider and the Gate-Control theory by Melzack and Wall.  There are various types of somatic and visceral nociceptors that can activate a somatic or visceral pain pathway. Neurochemical reactions at the site of injury activate the nociceptors which initiate an afferent impulse that enters the spinal cord, traverses specific ascending spinal tracts and reaches cerebral centers for interpretation. Nociceptive information is transmitted from the spinal cord to the thalamus and cerebral cortex along five ascending pathways. The intensity of pain sensation can be modulated at the periphery, the spinal cord, midbrain, and cerebral cortex,  by various mechanisms such as the Gate control theory, neurotransmitter substances such as enkephalin and endorphins, and descending pain modulatory systems.  This article summarizes the theories of pain, somatic and visceral pain, its pathways, viscero-somatic convergence, neurotransmitters of pain, pain syndromes and therapeutic modalities used for pain control.

 

Keywords: pain pathway, neurotransmitters of pain, pain receptors, pain syndromes

 

Introduction 

The International Association for the Study of Pain defines pain as, ‘An unpleasant sensory and emotional experience associated with actual or potential tissue damage’. The inability to communicate verbally does not negate the possibility that an individual is experiencing pain [1]. Pain is a neural-biochemical phenomenon where neurochemical reactions at the site of injury activate free nerve endings of nociceptors.  Modulation of afferent sensory information can occur at the periphery, the spinal cord, midbrain, and cerebral cortex [2].

 

Section 1: History of pain

For more than a century, views on the nature of pain sensation have been dominated by three major theories – the Specificity theory by Frey, the Intensivity theory by Goldscheider and the Gate-Control theory by Melzack and Wall [3].  Von Frey asserted that the skin consisted of a mosaic of discrete sensory spots and that each spot, when stimulated, gave rise to one sensation – either pain, pressure, warmth, or cold; in his view, each of these sensations had a different end organ in the skin and each stimulus-specific end organ was connected by its own private pathway to the brain.  Goldscheider argued that they simply represented pressure spots, a sufficiently intense stimulation of which could produce pain. Originally called ‘Intensitivity’ theory, it later became known as the Pattern or Summation theory. Refinements of the pattern and specificity concepts of pain were made in 1965, when Melzack and Wall pronounced their “Gate-Control” theory [4].

 

Section 2: Pain Receptors – Somatic and Visceral

Charles Sherrington discovered nociceptors which are pain receptors, most of which have free nerve endings that respond to stimuli that brings damage to the tissue [5]. It is thought that proteins present in their membranes convert thermal, mechanical or chemical energy of noxious stimuli into depolarizing electric potential. The cell bodies of nociceptors are located in dorsal root and trigeminal ganglia. Nociceptors may be somatic or visceral.

Somatic nociceptors can be divided into three major classes [6].

  1. Thermal nociceptors – are activated by extreme temperatures (>45 deg or <5 deg); have Aδ fibers and transmits fast pain.
  2. Mechanical nociceptors – are activated by intensive pressure applied on the skin and have Aδ fibers.
  3. Polymodal nociceptors- are activated by high-intensity mechanical, chemical or thermal stimuli (heat and cold); have non-myelinated C fibers and transmit slow, dull pain.

These three classes of nociceptors are widely distributed in the skin and deep tissues and often work together.

Visceral nociceptors – Visceral nociceptors can be divided into two distinct classes:

  1. “High-threshold” receptors – respond to mechanical stimuli such as stretch within the noxious range. These have been identified within many viscera, including the heart, lungs, gastrointestinal tract, ureter, and urinary bladder [7].
  2. “Intensity-encoding” receptors – the receptors encode the stimulus intensity in the magnitude of their discharges [8].

Viscera also contain silent nociceptor afferents [6,9,10]. Normally noxious stimulation does not activate these receptors, but inflammation and various chemical insults reduce their firing threshold dramatically such that they respond to previously innocuous stimuli.

 

Section 3: Factors that trigger Somatic and Visceral Pain receptors

Factors that stimulate somatic pain receptors are mechanical, thermal and chemical injury. However, factors that stimulate visceral receptors are not necessarily linked to tissue injury but include distension, ischemia, and inflammation. The sensitization of nociceptors after injury or inflammation, results from the release of a variety of chemicals such as bradykinin, histamine, prostoglandins, leukotrienes, acetylcholine, serotonin and substance P by the damaged cells and tissues in the vicinity of the injury [6]. Hollow organs such as the colon are very sensitive to luminal distension or inflammation but are totally insensitive to cutting or burning stimuli. Pain induced by colonic distension is dependent on the distending pressure rather than the volume [11]. The intraluminal pressure in the colon required to produce pain sensation is 40 to 50 mmHg. A tumor may continue to grow undetected if it fails to exert this intraluminal pressure and may cause pain only at a much later stage when there is complete obstruction of the lumen and a significant rise in intracolonic pressure. Solid organs are least sensitive, whereas serosal membranes of hollow organs are most sensitive.

 

Section 4: Pain Fibers (Including fast and slow fibers)

                                   Nerve fibers carrying pain sensation are of two types – “fast conducting Aδ fibers and slow conducting type C fibers. The fast-sharp pain signals are elicited by mechanical or thermal pain stimuli and are transmitted via thinly myelinated Aδ fibers to the spinal cord at velocities between 6 and 30 m/sec. Conversely, slow-chronic type of pain is mostly elicited by chemical types of pain stimuli but also at times by persisting mechanical or thermal stimuli. Slow pain is transmitted by non-myelinated type C fibers at velocities between 0.5 and 2 m/sec. Slow or chronic pain is generally dull, aching, burning or cramping and tends to become greater over time. Because of this double system of pain innervation, a sudden painful stimulus often gives a “double” pain sensation: a fast sharp pain that is transmitted by the Aδ fibers followed by slow pain that is transmitted by the C fibers [13]. For example, when you hit your toe against a stone, the initial sharp fast pain is transmitted by Ad fibers from mechanical nociceptors followed by a prolonged slow, dull pain via C fibers from polymodal nociceptors [6].

 

Section 5: The Traditional and newer concepts of Somatic and Visceral Pain pathways

There are two phylogenetic systems concerned with pain impulses:

  1. Phylogenetically old postsynaptic system (spino-reticulo-thalamic system) – where the impulses are transmitted via chains of short neurons to the reticular formation of the brain stem and also via the diffuse projection system of the thalamus to the cerebral cortex. 
  2. Phylogenetically new paucisynaptic system (spino-thalamo-cortical system) – where the impulses are transmitted via 3 orders of neurons: the 1st order neuron in the cerebrospinal ganglia; 2nd order neuron in the dorsal grey horn or spinal nucleus of trigeminal nerve; and 3rd order neuron in the specific relay nucleus of the thalamus.

 

5.1 Somatic pain pathway generally follows three orders of neurons. The first order neuron is situated in the dorsal root ganglia of spinal cord and trigeminal ganglia. Nociceptive afferent fibers carrying pain sensation terminate on nociceptive-specific neurons in lamina I (marginal layer), and lamina II (Substantia gelatinosa) of dorsal grey horn. Some fibers penetrate the grey matter and terminate in lamina V. Majority of the fibers terminate in the same spinal segment. Lamina V receives input from Aβ, Aδ and C fibers. Type C fibers carry nociceptive input from visceral structures. The convergence of somatic and visceral nociceptive input to lamina V neurons may explain “referred pain”, a condition in which pain from injury to viscera is predictably displaced to areas of the body surface. Neurons in the lamina VII of ventral horn respond to noxious stimuli from either side of the body. These neurons of lamina VII through their connections with the brain stem reticular formation, may contribute to the diffuse nature of many pain conditions [3,6].

Second order neurons sub serving pain sensation project contra laterally (and to a lesser extent ipsilaterally) to higher levels [3]. Nociceptive information is transmitted from the spinal cord to the thalamus and cerebral cortex along five ascending pathways [6]:

(1)  Spinothalamic tract

(2)  Spinoreticular tract

(3)  Spinomesencephalic tract

(4)  Cervicothalamic tract

(5)  Spinohypothalamic tract

 

The neospinothalamic tract is the most prominent ascending nociceptive pathway. It comprises of axons of nociceptive specific and wide dynamic range neurons that arise from laminae I, V and VII that project to the contralateral side and ascend in the anterolateral white funiculus to the thalamic nuclei. A few fibers of the neospinothalamic tract terminate in the reticular areas of the brain stem, but most pass to the thalamus without interruption [13]. In contrast, chronic pain moves along a different and slower tract called the paleospinothalamic tract. Though it follows the same path as the fast pain through the spinal cord, but once in the brain it separates and terminates in the hypothalamus and the limbic structures. The spinoreticular tract comprises of axons of neurons in laminae VII and VIII that ascend ipsilaterally and terminate in the reticular formation and thalamus. The spinomesenchephalic tract comprises of axons of neurons of laminae I and V that projects ipsilaterally to the mesencephalic reticular formation and periaqueductal gray, and via the spinoparabrachial tract tract to the parabrachial nuclei. In turn, neurons of the parabrachial nuclei project to the amygdala (a major component of the limbic system involved in emotion). Thus the spinomesenchephalic tract is thought to contribute to the affective component of pain. The spinohypothalamic tract projects to the autonomic control centers of the hypothalamus and is thought to activate complex neuroendocrine and cardiovascular responses [6].

                                   Recent work by Al-Chaer et al., has identified the dorsal column as being more important in visceral nociceptive transmission than the spinothalamic and spinoreticular tracts [14,15]. These newly identified pathways have led to new clinical approaches in managing visceral cancer pain. In humans, midline myelotomy (section of the midline transverse fibers of the spinal cord for the treatment of intractable pain, also known as commissural myelotomy, commissurotomy) has been used to treat visceral pain in pelvic cancer.

5.2 Visceral pain pathway: Viscerosensory information from the periphery is relayed by afferent fibers through sympathetic and parasympathetic nerves [8]. Thoracic nociceptive afferents travel to the thoracic splanchnics before converging onto the paravertebral sympathetic trunks and then enters the dorsal horn. Abdominal nociceptive afferents travel to the coeliac plexus and the thoracic splanchnics prior to entering the sympathetic trunks and dorsal horn. In contrast, the pelvic visceral nociceptor afferents converge on the pelvic splanchnic nerves, which are primarily parasympathetic fibers. Pelvic afferents also pass through the lumbar sympathetic splanchnic nerves. On entering the dorsal horn, visceral afferents terminate on lamina I and V. Visceral afferents constitute 10% of all afferent inflow into the spinal cord [8]. This is a relatively small number when considering the large surface area of some organs. However, the number of dorsal horn neurons that respond to visceral stimulation is estimated to be 56% to 75%, suggesting functional divergence of these neurons. There are no neurons that respond exclusively to visceral afferents.

5.3 Pain pathway from the face

The fibers conveying pain sensation have their cell bodies located in the ganglia of the V, VII, IX and X cranial nerves. Their central processes end in the caudal part of spinal nucleus of trigeminal nerve and even in the bulbar reticular substance [16]. Three ascending pathways from this nucleus have been identified:

1)          A polysynaptic pathway with a bilateral distribution to the reticular formation of the brain stem and the diffuse thalamic system.

2)          A fast pathway with a bilateral distribution ending in the ventro-postero-medial nucleus (VPM) of the thalamus and also in the diffuse thalamic system.

3)          An intranuclear pathway within the trigeminal nucleus [17, 18].

5.4 Thalamus

Two main regions in the thalamus process nociceptive information, the medial and lateral nuclear groups. The lateral nuclear group has the Ventroposterior medial and ventroposterior lateral nucleus. These lateral group nuclei receive input via the spinothalamic tract and are concerned with mediating information regarding the location of injury. The medial nuclear group has the central lateral nucleus and Intralaminar complex. Its major input is from neurons of laminae VII and VIII. This pathway is often called the paleospinothalamic tract (also as spinoreticulothalamic tract) because it includes polysynaptic inputs via the reticular formation of the brainstem [6]. From the thalamic areas the signals are transmitted to other basal areas of the brain as well as the somatosensory cortex.

 

5.5 Cortical Centres for Pain

Neurons in several regions of the cerebral cortex respond selectively to nociceptive input. These include the somatosensory cortex, the cingulate gyrus and the insular cortex. Presently there is adequate evidence to show that the projection of fast pain is to the lower part of the somatic sensory cortex SI (Brodman’s area 3,1,2) and slow pain is to the somatic sensory area SII of the cortex, anterior part of insula and the cingulate gyrus. The cingulate gyrus being part of the limbic system is thought to be involved in the emotional component of pain. The insular cortex contributes to the autonomic component of the overall pain response [6]. The fast-sharp type of pain can be localized much more exactly than slow-chronic pain [13].

 

Section 6: Neurotransmitters of Pain

Synaptic transmission between the central process of nociceptive afferent fibers and dorsal horn neurons is mediated by chemical neurotransmitters. These include:

  1. Glutamate – is the major neurotransmitter released from synaptic vesicles in primary afferent terminals of Aδ and C fibers having a duration of action lasting only few milliseconds. The actions of glutamate released from the sensory terminals are confined to postsynaptic neurons in the immediate vicinity of the synaptic terminal due to the efficient reuptake of amino acids into glial cells or nerve terminals [6].
  2. Neuropeptides –released from sensory terminals can diffuse considerable distances away from their site of release because there is no specific reuptake mechanism. Thus, its release is likely to influence many postsynaptic dorsal horn neurons. This feature together with the fact that peptides are significantly increased in persistent pain conditions, suggests the unlocalized character of many pain conditions [6].
  3. Substance P is released from C fibers in response to tissue injury or to intense stimulation of peripheral nerves [6]. It produces prolonged post-synaptic excitation.

 

Section 7: Factors That Modify Pain Input

There are several factors that modify pain input:

  1. Gate control theory
  2. Neurotransmitter substances such as enkephalin and endorphins
  3. Descending pain modulatory systems from the brain stem to the spinal cord

 

Gate Control Theory: The gate control theory incorporates the idea that pain results from the balance of activity in nociceptive and non-nociceptive afferents [6]. Melzack and Wall (1965) observed in decerebrate and spinal cats, that peripheral stimulation of large myelinated fibers produced a negative dorsal root potential and that stimulation of small C fibers causes a positive root potential. They postulated that these potentials modulated the activity of neurons in the dorsal horn [4]. Simply put, non-nociceptive afferents “close” and nociceptive afferents “open” a gate to the central transmission of noxious input. A medical therapy designed to activate the gate control mechanism is transcutaneous electrical nerve stimulation (TENS). Electrodes are used to activate large diameter afferent fibers that overlap areas of injury and pain. The application of electrical stimuli to the skin reduces pain by stimulating touch fibers [6,19].

 

Neurotransmitter substances: Evidence based on both human and animal studies has shown that an endogenous system lying within the central nervous system induces a certain degree of analgesia. Opiate alkaloids such as morphine in low doses produces a powerful analgesia by inhibiting nociceptive neurons in the dorsal grey and periaqueductal grey. Opioid receptors are present in the periaqueductal grey matter, thalamus, ventral medulla and substantia gelatinosa of the spinal cord. Endogenous opioid peptides are encephalins, β-endorphins and dynorphins.  β-endorphins are released into the bloodstream in response to stress and suppress pain sensation [3,6].

 

Descending pain modulatory pathways: Several descending pathways suppress the activity of nociceptive neurons in the dorsal grey horn of spinal cord. Electrical stimulation of certain sites, such as periaqueductal grey matter, raphe nucleus magnus, mesencephalic and medullary reticular formation including the parabrachial region produces a profound and selective analgesia. These neuronal groups and their connections constitute an endogenous analgesic system. Other forebrain sites, which inhibit spinothalamic tract cells, include the periventricular grey matter, VPL nucleus of thalamus, primary sensory (SI) and posterior parietal cortices [6, 20].

 

 

Section 8: Types of Pain

Central and peripheral neuropathic pain: peripheral neuropathic pain occurs following damage to a peripheral nerve whereas Central pain occurs when the lesion affects the central nervous system such as the spinothalamic tract or thalamus. E.g. An infarct in the VPL nucleus of thalamus produces thalamic or Dejerin-Roussy syndrome, which causes spontaneous burning pain and dysesthesia [6].  

 

Nociceptive pain: results from direct activation of nociceptors in the skin or soft tissue in response to tissue injury.  

 

Somatic Cancer Pain: Somatic cancer pain can be caused by neoplastic invasion of bone, joint, muscle or connective tissue, bone fractures, radio/chemotherapy-induced pain syndromes and post-surgical pain. The tumor produces and stimulates local production of inflammatory mediators like TNF causing stimulation of peripheral nociceptors.

 

Visceral Cancer Pain: Viscera are insensitive to pain. Solid organs such as lung, liver, and kidney parenchyma are insensitive, despite gross destruction by malignancy. Pain is signaled only when capsular or adjacent structure is involved. Visceral pain may be accompanied by autonomic reflexes such as nausea [21].

 

Bone Pain: Bone pain is typically dull, exacerbated by weight-bearing and movement. Nociceptors are concentrated in the periosteum, whereas bone marrow and cortex are less sensitive to pain. Neoplastic bone pain is caused by stretching of periosteum by tumor expansion, microfractures, nerve compression and release of algesic substances from the bone marrow [22,23,24]. Bone pain has also been correlated with osteoclastic activity [25].  

 

Referred pain: the best example is pain of myocardial ischemia where pain is referred to the neck, shoulders and left arm. Electrophysiologic experiments demonstate that somatic and visceral nociceptive input converge on the same region of dorsal grey horn known as viscerosomatic convergence [8]. The patient projects pain from the viscera to an area supplied by the corresponding somatic afferent fibers.

 

Typical Facial pain (Trigeminal neuralgia): Variety of diseases may affect the peripheral branches and ganglia of the trigeminal nerve causing trigeminal neuralgia (tic douloureux). The nature of the pain, its unilaterality, its tendency to involve the second and third divisions of the trigeminal nerve, an intensity that makes a patient grimace or wince (tic) following a trigger point, the lack of demonstrable sensory or motor deficit, and its response in more than half the cases to carbamazepine or phenytoin are characteristic [3].

 

Muscle pain: Muscle pain is a common medical complaint. Mechanical pain results from excessive muscle tension or contraction. Inflammatory pain results from disruption of muscle fibers, inflammatory exudate and fiber swelling. Ischemic muscle pain results from metabolic change usually in response to exercise [3].

 

Allodynia, Hyperalgesia,and sensitization: Pain due to a stimulus which does not normally cause pain is called allodynia. An increased response to a stimulus which is normally painful is called hyperalgesia. Upon repeated application of noxious mechanical stimuli, nearby nociceptors that were previously unresponsive to mechanical stimuli now become responsive, a phenomenon called sensitization.

 

Phantom limb pain: occurs in 10% of patients following amputation of a limb. It is of a continuous burning quality and is caused by a neuroma. The patient ‘feels’ the pain arising from some point on the missing limb. Treatment often responds to simple measures such as tri-cyclic antidepressants.

 

Section 9: Pharmacotherapy of Pain

Visceral and somatic pain can be managed by pharmacological and interventional techniques. Combinations of opioids such as morphine, NSAIDs, and adjuvant medications form the mainstay of therapy. When pharmacological therapies prove ineffective, regional anesthesia techniques or neurosurgical techniques should be considered. Regional anesthesia involves administration of local anesthetics, opioids, or neurolytic agents to the neural axis or visceral plexi. The goals of these interventional procedures are to provide superior analgesia and decrease in opioid consumption. Continuous epidural or intrathecal infusion of local anesthetics or opioids can be effective for controlling abdominal or pelvic cancer pain. By adding local anesthetic to the opioids, the analgesic effect is improved [26]. Neurolytic block of coeliac plexus is indicated for visceral cancer pain in the upper abdomen, especially pancreatic in origin [27].  Pelvic pain due to tumor invasion can be managed by neurolysis of  superior hypogastric plexus, while perineal pain due to pelvic cancer can be eased by blockade of the ganglion impar [28]. Ablative neurosurgical techniques are used less often than in the past, but for patients with refractory unilateral cancer pain, percutaneous cordotomy may still be useful. The recently described dorsal column pathway may also offer therapeutic options for the future. The treatment of choice for metastatic bone pain is radiation therapy. It acts by reducing local inflammation and tumor shrinkage [26]. Bone-specific radioisotopes such as strontium-89 are preferentially taken up at sites of osteoblastic activity [27]. Uptake is greatest in patients with widespread metastases, as happens in bone metastases secondary to prostatic carcinoma.

 

Section 10: Conclusion

Nociception is not primarily a pathological phenomenon, but serves a protective function. Conditions with loss of pain perception such as leprosy or hereditary sensory neuropathy exemplify this. Even though pain has serves a protective and warning mechanism, crippling and persistent pain is the most feared symptom that medical science would one day be able to conquer.

Acknowledgments

            There is no conflict of interest and no financial gain in the preparation of this manuscript.

 

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