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Pain Sensation: Nociceptive receptors and transduction

Pain is a subsystem of somatic sensation which includes a wide range of unpleasant sensory and emotional experiences usually associated with actual or potential tissue damage (Das et al., 2005).

Over the years, by means of the evolutive process of natural selection, nature has made sure that pain is a bodily signal we cannot ignore. As a matter of fact, sensitivity and reactivity to noxious stimuli are essential to the well-being and survival of an organism. In dangerous circumstances pain “tells” the subject to get out of that situation immediatly, this is its main function. Without these attributes provided by pain mechanisms, the organism would have no means to prevent or minimize dangerous circumstances (individuals congenitally insensitive to pain are easily injured and most of them die at an early age1).

While most of the sensory and somatosensory modalities are primarily informative, pain is a “protective modality”. Pain perception (also called nociception) doesn’t come from excessive stimulation of the same receptors that generate somatic sensations, as someone could even think, it is a properly devoted subsystem. Nociception (from the Latin nocere, “to hurt”) in fact depends on specifically dedicated receptors and, due to its vital importance, this kind of information travels through redundant pathways.

Pain also differs from the classical senses (hearing, smell, taste, touch, and vision) because it is both a discriminative sensation and a graded emotional experience.

In the big picture, pain appears as a more complex whole experience than simple somatic sensation; that is why there are still many obscure aspects not completely understood, especially in the field of pain physiology and pharmacology. For this and other reasons, even nowadays, nociception remains an extremely active area of scientific research.

2. Pain Sensation

- Nociceptive receptors and transduction

Pain sensation begins with relatively unspecialized “free” nerve cell endings called nociceptors. Like other somatic sensory receptors, they transduce a variety of noxious stimuli into receptor potentials, which in turn trigger action potentials in the pain nerve fibers (afferents). These action potentials are transmitted to the spinal cord and then, through the brainstem, to the thalamus and the somatic sensory cortex according to specific pathways2.

Nociceptors are widespread distributed, they also show different degrees of sensitiveness and specialization. There are nociceptors in the skin, in the joints and also in visceral organs, but none of them is found inside the central nervous system (CNS)1.

In contrast with somatic sensory receptors (responsible for the perception of innocuous mechanical stimuli), the axons associated with nociceptors conduct relatively slowly, being only lightly myelinated or, more commonly, unmyelinated2. Thus, according to the different kind of axon, there are faster or slower pain pathways. In particular, pain receptors can fall into four major categories depending on their response to the different types of stimulation caused by the damage:

mechanosensitive nociceptors: respond to mechanical stimulation and have A-delta fibers, bigger axons with faster conduction velocity;

mechanothermal nociceptors: respond to thermal stimuli, A-delta fibers;

chemical nociceptors: respond to chemical substances, A-delta fibers;

polymodal nociceptors: respond to high intensity stimuli of the previous three types and have C fibers, smaller and unmyelinated axons with slower conduction velocity.

The cell bodies of these primary pain-neurons are located in the dorsal root ganglia (for body afferents) and in the trigeminal ganglia (for face afferents)1,2.

The transduction of nociceptive signals, which starts with the nociceptive receptors, is a complex task. Tissue damage results in the release of a variety of chemical substances which triggers the response of nociceptors. Some of these substances activate the transmembrane transient receptor potential (TRP) channels, which in turn initiate action potentials2.

Another characteristic feature of nociceptors is their tendency to be sensitized by prolonged stimulation, making them respond to other sensations as well in certain circumstances. This prolonged stimulation increases the release of chemical substances, making nociceptors sensitized and reducing their response threshold. Actually, within a few seconds after the injury, an area of some centimeters around the injured site shows reddening caused by vasodilation. This inflammation becomes maximal after about ten minutes and this region shows a lowered pain threshold (hyperalgesia) in response to additional noxious stimuli. This effect is also referred to as peripheral sensitization, in contrast to central sensitization that can occur at higher levels in the dorsal horn1.

Although it is still unknown whether nociceptors respond directly to the noxious stimulus or indirectly by means of one or more endogenous chemical intermediaries released from the traumatized tissue, the activation of nociceptors initiates the process by which pain is experienced: these receptors relay information to the CNS about the intensity and location of the painful stimulus.

- Pain classification

The result of sudden painful stimulation can be divided into two categories of sequential sensations separated by a short time interval. A sharp “first pain”, immediately after the damage, it’s followed some seconds later by additional, diffuse and longer-lasting “second pain” sensation. The temporal interval between these two separate sensations is due to the difference between fast transmitting A-delta fibers and slow transmitting C fibers. This phenomenon is also known as “double pain sensation”.

Pain has also been classified into three major types1:

Pricking pain: is also called fast pain or sensory pain (first pain) and arises mainly from the skin, carried by A-delta fibers which permit discrimination and localization of the pain.

Burning pain: is caused by inflammation, burned skin and is carried by C fibers. This type of pain is a more diffuse, slower to onset, and longer in duration (second pain). Like pricking pain, burning pain arises mainly from the skin, but it is not distinctly localized.

Aching pain: is a sore pain which arises mainly from the viscera and somatic deep structures. This pain is carried by the C fibers from the deep structures to the spinal cord and is not distinctly localized.

- Pain pathways

The neural pathway that conveys pain (and temperature) information from the periphery of the body to the higher centers of the CNS is often referred as the anterolateral system (or ventrolateral column). This pathway is physically separated from the system that conveys mechanosensory information like touch and pressure (dorsal column-medial lemniscus pathway). However, even though the dorsal route has been always considered a "touch pathway" functionally separate from the anterolateral pathway, recent reports indicate that the dorsal column can carry noxious information from the viscera and widespread skin regions as well1.

Anyway, the main difference between these two systems remains the site of decussation: while the dorsal column is an ipsilateral tract until the medulla (where synapses and decussates), the anterolateral system makes early synaptic connections and decussates right away in the spinal cord, becoming a contralateral tract.

Composing the anterolateral system, there are three major ascending tracts: the neospinothalamic tract (the main, central pain pathway, phylogenetically younger, with few synapses), the paleospinothalamic tract and the archispinothalamic tract (which constitute minor parallel pain pathways, phylogenetically older and multisynaptic tracts)1.

Every pain tract is made of three kinds of pseudounipolar neurons: first-order, from free nerve endings (nociceptors) to the dorsal horns of the spinal cord; second-order, from the dorsal horns to the thalamus; and third-order, from the thalamus to the primary somatic sensory cortex.

The cell bodies of first-order neurons are located in the dorsal root ganglia (DRG) for all three pathways.

a) The neospinothalamic tract (central pathway) constitutes the classical anterolateral system. This pathway is responsible for the immediate awareness of a painful sensation and for the understanding of the exact location of the painful stimulus.

The first-order nociceptive afferents enter the spinal cord via the dorsal roots of the DRG and, when these projecting axons reach the dorsal horns of the spinal cord, they branch into ascending and descending collaterals, forming the tract of Lissauer2. Once within the dorsal horn, these afferents make synaptic connections with second-order neurons located in Rexed’s laminae (layer I to V). Axons of these second-order neurons then cross the midline of the spinal cord, decussating in the anterior white commissure, and ascend to the brainstem in the contralateral (anterolateral) quadrant.

Most of the pain fibers from lower extremities of the body and below the neck terminate, through the brainstem, in the ventral posterior lateral nucleus (VPL) of the thalamus. The VPL, which serves as a relay station, is thought to be mainly concerned with discriminatory functions1. Finally, here axons of second-order neurons synapse with third-order neurons that send the signal to the primary and secondary somatosensory cortex (SCI and SCII, respectively).

Unlike the rest of bodily afferents, first-order nociceptive neurons from the head, face and intraoral structures have somata in the trigeminal ganglion. Trigeminal fibers enter the pons, descend to the medulla (forming the spinal trigeminal tract) and make synaptic connections in the spinal trigeminal nucleus, then cross the midline and ascend as trigeminothalamic tract (or trigeminal lemniscus). Axons from the second-order neurons terminate in a variety of targets in the brainstem and thalamus, but the discriminative aspects of facial pain are thought to be mediated by projections to the ventral posterior medial nucleus (VPM) of the thalamus and by projections (from here) to primary and secondary somatosensory cortex2.

All of the fibers terminating in VPL and VPM are somatotopically oriented and still here the information supplied by different somatosensory receptors remains segregated. Axons from the thalamus synapse with third-order neurons of the SCI, which includes Brodmann’s Areas 3a, 3b, 1 and 2. Each of these cortical areas contains a separate and complete representation of the body: they are somatotopically organized maps representing the human body (from the foot up to the face) in a medial to lateral arrangement2.

b) The paleospinothalamic tract is a parallel pathway where the emotional response to pain is mediated1. This tract also activates brainstem nuclei which are the origin of descending pain-suppression pathways which regulate the sesation of noxious inputs at the spinal cord level.

In the paleospinothalamic tract the majority of the first-order nociceptive neurons make synaptic connections with second-order neurons in Rexed’s layer II (substantia gelatinosa). These second-order neurons also receive input from mechanoreceptors and thermoreceptors, and that’s why the anterolateral system is also responsible for temperature perception1.

The nerve cells that compose the paleospinothalamic tract are multireceptive or wide dynamic range nociceptors. Most of their axons cross and ascend in the spinal cord primarily in the anterior region and thus form the anterior spinal thalamic tract (AST). These second-order fibers contain several tracts and each of them makes a synaptic connection in different locations: in the mesencephalic reticular formation (MFR) and in the periaqueductal gray (PAG), forming the spinoreticular tract; in the tectum, also known as the spinotectal or spinomedullary tract; in the midline thalamic nuclei, forming the spinothalamic tract. Altogether these three fiber tracts are thus known as the paleospinothalamic tract, which is in part bilateral, because some of the ascending fibers do not cross to the opposite side of the cord1. Finally, from the thalamic nuclei, these fibers synapse bilaterally in the somatosensory cortex.

Pain is a complex experience processed by a diverse and distributed network of neurons and brain regions. In addition to the sensory-discriminative aspects (carried by the neospinothalamic tract) there are also affective-motivational components of pain2. In the paleospinothalamic pathway there are extensive connections between the thalamic nuclei and the limbic areas such as the cingulate gyrus and the insular cortex. The insular cortex integrates the sensory input with the cognitive components. The limbic structures (amygdala, superior colliculus) project to the hypothalamus and initiate visceral responses to the pain. The thalamic nuclei also projects to the frontal cortex, which in turn is linked to the limbic structures involved in processing the emotional components of pain1.

c) The archispinothalamic tract is another parallel pathway, phylogenetically the oldest that carries noxious information1. The characteristics of this tract are very similar to the ones found in the previous pathway.

First-order nociceptive neurons make synaptic connections in Rexed’s layer II (substantia gelatinosa). From here, second-order fibers ascend and descend in the spinal cord surrounding the grey matter to end synapsing with cells in the reticular formation and in the periaqueductal gray. Further diffuse multisynaptic pathways ascend to the diverse nuclei of thalamus and send collaterals to the hypothalamus as well as the limbic system nuclei. These fibers, like for the paleospinothalamic tract, mediate visceral, emotional and autonomic reactions to painful stimuli.

In short, because of the importance of warning signals of dangerous circumstances, several nociception pathways are involved to transmitting these signals and some of them are redundant.

The neospinothalamic tract conducts fast pain (via A-delta fibers) and provides information of the exact location of the noxious stimulus. The multisynaptic paleospinothalamic and archispinothalamic tracts conduct slow pain (via C fibers), a pain which is chronic and harder to localize. Through these patways, pain activates many different brain areas which link together sensation, perception, emotion, memory and motor reaction1.

3. Pain Modulation

When talking about pain, we always have to consider and keep in mind the discrepancy between the objective reality of a painful stimulus and the subjective rsponse to it. Modern studies have provided considerable insight into how circumsatnces affect pain perception-interpretation and, ultimately, into the pharmacology of the pain system2.

For many years it has been suggested that somewhere in the CNS there should be some neuronal circuits modulating incoming painful informations. Evidence for an intrinsic analgesia system was demonstrated by intracranial electrical stimulation of certain brain sites1,3. The circuit consisting of the periaqueductal gray matter (PAG), the raphe nuclei (RN), the locus coeruleus (LC) and the caudate nucleus (CN) contributes to the descending pain suppression mechanism, which inhibits incoming pain information at the spinal cord level6. Stimulation of such areas produce analgesia without behavioral suppression; indeed, touch, pressure and temperature sensation remain intact1. At the interneuronal level, opiate receptors activation causes hyperpolarization of the neurons, which in turn results in the inhibition of firing and in the release of substance P (a neurotransmitter involved in pain transmission) that blocks pain transmission1.

In addition to descending projections, also local interactions between mechanoreceptive afferents and neural circuits within the dorsal horn can modulate the transmission of nociceptive informations to higher centers2. Observations by Melzack and Wall led to the idea that concomitant activation of the large myelinated fibers associated with low-threshold mechanoreceptors can mediate the flow of pain. This mechanism, also known as “Gate Control Theory”13, predicts that (at the spinal cord level) non-noxious stimulation will produce presynaptic inhibition on dorsal root nociceptor fibers and thus blocking incoming noxious information from reaching the CNS1 (i.e. non-painful input closes the gates to other painful inputs, which results in prevention and suppression of pain sensation).

This explains also why if you, for example, stub a toe, a natural and effective reaction is to vigorously rub the site of injury for a couple of minutes2.

However, there are many different factors that can influence the way we understand pain. Doubtless, three of these are: drugs, prior injuries and, more broadly speaking, circumstances.

a) Drugs

The brain has a neuronal circuit and endogenous substances to modulate pain. There are two primary types of drugs that work on the brain: analgesics and anesthetics1. The term analgesic refers to a drug that relieves pain without loss of consciousness, whereas the term anesthetic refers to a drug that depresses the CNS. Anesthetics are characterized by the absence of perception for all sensory modalities, including loss of consciousness, but without loss of vital functions.

The areas that produce analgesia when stimulated are also responsive to exogenously administered opiate drugs2. As a matter of fact, the most effective clinically used drugs for producing temporary relief from pain are the opioid family, which includes morphine and heroin1. Unluckily, several side effects resulting from opiate use include tolerance and drug dependence (addiction). In general, these drugs modulate the incoming pain information as well as relieve pain temporarily, and are also known as opiate producing analgesia (OA).

Opioidergic neurotransmission is found throughout the brain and spinal cord and appears to influence many CNS functions: opioids exert marked effects on mood, cognition and motivation1 (e.g. producing euphoria).

The analgesic action of opiates implied the existence of specific brain and spinal cord receptors for these drugs long before the receptors were actually found. Since such receptors are unlikely to have evolved in response to the exogenous administration of opium and its derivates, the convinction grew that endogenous opiate-like compounds must exist in order to explain the evolution of these receptors in the body2. Nowadays, three classes of opioid receptors have been identified: μ (mu), δ (delta) and κ (kappa). All three classes are widely distributed in the brain, and particularly in the PAG, which is the site for higher cortical control of pain modulation in humans8. Moreover, three major classes of endogenous opioid peptides that interact with them have been recognized in the CNS: β-endorphins, enkephalins and the dynorphins. Enkephalins are considered the putative ligands for the δ receptors, β endorphins for the μ-receptors, and dynorphins for the κ receptors1.

The opioid peptides modulate nociceptive input mainly in two ways: blocking neurotransmitter release by inhibiting Ca2+ influx into the presynaptic terminal; or opening potassium channels, which hyperpolarizes neurons and inhibits spike activity. The various types of opioid receptors are distributed differently within the central and peripheral nervous system and this can explain many unwanted side effects following opiate treatments1. (For example, μ-receptors are widespread in the brain stem parabrachial nuclei, which is a respiratory center. Inhibition of these neurons elicits also respiratory depression).

In addition to opiates, the other big family of analgesia producing drugs is represented by the cannabinoids. Like opiates, cannabinoids produce analgesia when microinjected in the PAG and pain itself serves as a trigger for endocannabinoid release3. Results from the study by Walker et al. (1999) indicate that anandamide (an endogenous cannabinoid) fulfills the requirements for a nonopiate mediator of endogenous pain suppression and these data support the existence of endogenous cannabinergic circuitry in the dorsal and lateral PAG. Even if the opiate and cannabinoid mechanisms partially overlap anatomically, the endogenous opiate system is activaetd by intense and prolonged stimuli (such as high threshold electrical stimulation), while endogenous cannabinoids occur mostly in tonic pain suppression, during tests that do not produce significant stress or fear3.

Cannabinoids have been used to treat pain for centuries and cannabis is still used despite its illegal status in most parts of the world. The spontaneous and stimulated release of anandamide in a pain-suppression circuit suggests that such drugs may form the basis of a modern pharmacotherapy for pain, particularly in instances where opiates are ineffective3.

b) Previous injury

A curious effect, well known and documented in clinical literature, is referred to as phantom limb sensation. Following the amputation of an extremity, nearly all patients have an illusion that the missing limb is still present. Although this illusion usually diminishes over time, it persists in some degree throughout the amputee’s life, and can often be reactivated2. A reasonable explanation for this phenomenon is that the central sensory processing apparatus continues to operate indipendently of the periphery, giving rise to these bizarre sensations. Indeed, considerable functional reorganization of the somatotopic maps in the primary somatosensory cortex occurs immediately after the amputation and tends to evolve for several years2. Neurons that have lost their original inputs respond to tactile stimulation of other (near) body parts, and so it is not unusual for the patient to perceive a phantom limb as a whole and intact, but displaced from the real location. These and further evidences suggested then that a full representation of the body exists indipendently of the peripheral elements that are mapped2.

Anyways, the major problem following phantom limbs phenomena is constituted by the fact that up to 85% of the amputated patients develop also phantom pain4. The description of this common unease can vary from a tingling or burning sensation to some more serious and debilitating issues. Phantom pain, in fact, is one of the more frequent causes of chronic pain syndromes and is extraordinarily difficult to treat2. Neverthless there is no really effective treatment, a study by Jahangiri et al. (1994) demonstrated that preoperative epidural infusion of morphine, bupivacaine and clonidine significantly reduces the incidence of phantom limb pain and phantom limb sensation. Moreover, this kind of treatment has been shown as safe for use on general surgical wards with a low incidence of minor side-effetcs4.

Other than amputations, pain perception may also be modulated in certain stressful situations. Exposure to a variety of painful or stressful events produces an analgesic reaction, and this phenomenon is called stress induced analgesia (SIA). It has been considered that SIA can provide insights into both the psychological and physiological factors that activate endogenous pain control and opiate systems1. (For example, soldiers wounded in battle or athletes injured in sports events sometimes report that they do not feel pain during the battle or game; however, they will experience the pain later after the battle or as game has ended).

Some studies demonstrated in animals that electrical shocks cause stress-induced analgesia3 and it has been suggested that endogenous drugs, (opiates or cannabinoids) released in response to stress, inhibit pain by activating the midbrain descending system1.

Based on these and other experiments, it is assumed that the stress experienced by the soldiers and the athletes suppressed the pain which they would later perceive.

c) Circumstances

The experience of pain is highly variable between individuals: this highly subjective perception has a complex and often non linear relationship between nociceptive input and pain sensation5. From human experimentation we know that a variety of pain modulatory mechanisms exist in the nervous system, and these systems can be accessed either pharmacologically or through contextual and cognitive manipulation7,6. Various mental processes such as attention, emotional state, past experiences, memories, beliefs and feelings have been shown to influence pain perception and bias nociceptive processing in the humain brain9. All these “top-down” factors can be grouped together in the category of circumstances that either enhance or diminish pain sensation in regard to dedicated modulatory circuits.

Among the cognitive variables influencing pain, the brain mechanisms underlying attentional control have been probably the most extensively studied5. A number of reports show the important role of attentional state in modulating the activity of primary somatosensory areas7. Thus, pain is perceived as less intense when individuals are distracted from it, as proved in an interesting study by Das et colleagues (2005). This research provides strong evidence supporting virtual reality (VR) based games in providing analgesia and positive influence on children with acute burn injuries, with minimal side effects10. VR can be considered an intermediary between reality and computer technology, and its ability to immerse the user interacting with the artificial environment is central in this kind of approach.

However, attentional processes interact with mechanisms supporting the formation of expectations about pain and reappraisal of the experience5. The ability to predict the likelihood of an aversive event is an important adaptive capacity11. Our subjective sensory experiences are thought to be heavily shaped by interactions between expectations and incoming sensory information12 and this cognitive factor is important also for pain perception: positive expectations (i.e., expectations for decreased pain) produce a reduction in perceived pain that rivals the effects of a clearly analgesic dose of morphine12. These evidences provide also a neural mechanism that can, in part, explain the positive impact of optimism in chronic disease states. In fact, perceived control, attentional control and the descending pain modulatory system are involved in the placebo-induced analgesia, which is a clinical example of cognitive pain modulation that decreases pain intensity and cerebral responses to pain5. Such “top-down” modulatory mechanism is a robust and clinically important phenomenon, which can be demonstrated in approximately one-third of the population9. Moreover, placebo analgesia requires the activation of endogenous opioid-mediated inhibition and neuroimaging techniques showed that there is also overlapping among brain sites activated by opioids and those that are activated during placebo analgesia9.

Also the emotional state driven by the (experimental) context alters the attitude of patients and can produce powerful effects on pain perception7. In general, negative emotions increase pain, whereas positive ones decrease it14,7. Neverthless the brain mechanisms underlying these effects remain largely unknown, the prefrontal cortex, as well as parahippocampal and brainstem structures, are thought to be involved in the emotional regulation of pain14. According to Roy et al. (2009) cognitive and emotional processes induced by pleasant or unpleasant pictures interact with pain perception and modulate the responses to painful electrical stimulations in the right insula, paracentral lobule, parahippocampal gyrus, thalamus, and amygdala14. Not only, recent studies suggested that emotionally laden images representing human pain had a unique capacity to enhance pain reports15, in the suggestive perspective that search for the neural bases of human empathy with huge social implications.

Thus, even though is well-established that mood selectively alters the affective-reactive response to pain (also called pain tolerance), the interpretation for some of these studies is sometimes difficult, since they do not always clearly dissociate changes in mood from changes in attention7. In fact, other studies showed that emotions can have a direct effect on attention to pain, leading to what is called “attentional bias” toward pain-related informations, which does not ensure the absence of covariate processes7.

In the end, the available data indicate that emotion and selective attention may both interact modulating pain perception and cortical responses. But the observations that emotional manipulations alter pain unpleasantness more than pain sensation, while attention alters both pain sensation and unpleasantness, suggest that different modulatory circuits are involved7 and that they act through at least partially distinct mechanisms, which can be separated by appropriate experimental settings15.

All this multiplicity of mechanisms underlying the emotional modulation of pain is reflective of the strong and reciprocal interrelations between pain and emotions, and emphasizes even more the powerful effects that emotions can have on pain perception14.

4. Conclusions

In conclusion, in the CNS, much of the information from the nociceptive afferent fibers results from excitatory discharges of multireceptive neurons. The pain information in the CNS is controlled by ascending and descending inhibitory systems that can exert both facilitatory and inhibitory effects on the activity of neurons using endogenous opioids or other substances as mediators. In addition, a powerful inhibition of pain-related information occurs in the spinal cord. These inhibitory systems can be activated by brain stimulation, intracerebral microinjection of morphine, and peripheral nerve stimulation1.

However, pain is an extremely complex perceptual and cognitive experience that is influenced also by many “top down” factors such as past sensations, expectations, the context within which the noxious stimulus occurs, the attentional and emotional state. Therefore, for all these reasons, the response to pain can often vary considerably from subject to subject.

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