Lamina 1 Flashcards
Outline the two groups of nociceptive c fibres
Nociceptive C fibres can be divided into two major neurochemical groups: those that contain neuropeptides, such as substance P, and those that do not. These two groups have distinctive termination zones within the superficial laminae. Non-peptidergic C fibres are mainly associated with the skin, where they innervate the epidermis, whereas peptidergic fibres innervate various other tissues as well as deeper regions of the skin.
Which c fibres express MRGPRD? Where does the axons of these c fibres terminate peripherally and centrally?
Expression of Mas-related G-protein coupled receptor member D (MRGPRD), a sensory neuron-specific G protein-coupled receptor, has recently been shown to define a population of non-peptidergic nociceptive C fibres in the mouse (Zylka et al., 2005). They have axons that terminate peripherally, in the epidermis, and centrally, in a narrow band within lamina II.
Spinal neurons respond to peripherally generated signals. How are these controlled and modulated?
Spinal neurones, which respond to these peripherally generated signals, are under ongoing control by peripheral inputs, interneurones, and descending controls. One consequence of this modulation is that the relationship between stimulus and response to pain is not always straightforward.
What differences are there in NT release between acute and sustained noxious stimuli?
Glutamate is released from sensory afferents in response to acute noxious stimuli, and it is fast AMPA receptor activation that is responsible for setting the initial baseline response of spinal dorsal horn neurones to noxious stimuli. However, if a repetitive and high-frequency stimulation of C-fibres occurs, there is then an amplification and prolongation of the response of spinal dorsal horn neurones to subsequent inputs, known as wind-up. This enhanced activity results from the activation of the NMDA receptor. If there are only acute or low-frequency noxious or tactile inputs to the spinal cord, then activation of the NMDA receptor is not possible, since under normal physiological conditions the ion channel of this receptor is blocked by the normal levels of magnesium ions (Mg2+) found in nervous tissues. This unique Mg2+plug of the channel requires a sustained depolarization of the membrane in order to be removed and allow the NMDA receptor-channel to be activated and opened. Here, it is likely that the co-release of peptidergic transmitters, such as substance P and CGRP, which are found in C-fibres along with glutamate, is responsible for a prolonged slow depolarization of the neurone and subsequent removal of the NMDA block, thus permitting wind-up to occur.
Price et al., 1994
NMDA receptor activation has been clearly shown to play a key role in the hyperalgesia and enhancement of pain signalling seen in more persistent pain states including inflammation and neuropathic conditions
How does NMDA receptor activation result in central sensitisation?
The major mechanism by which the NMDA receptor acts is through the large influx of calcium ions (Ca2+) occurring when the channel is activated. Once inside the cell, Ca2+ can activate various effectors and promote downstream changes. Such effectors include neuronal nitric oxide synthase, calcium/calmodulin-dependent kinases (CaMKI/II), and ERK, which can promote mechanisms of plasticity such as long-term potentiation (LTP). Similar plastic mechanisms occur after, peripheral nerve damage, and inflammation, and can result in the elevated responsiveness and activity of dorsal horn neurones. This phenomenon, termed central sensitization, manifests in the patient as an increased response to painful stimuli (hyperalgesia), and pain resulting from normally non-painful tactile stimuli (allodynia). Overall, the NMDA receptor is critical for both the induction and the maintenance of the pain. Therefore, the targeting of NMDA signalling with pharmacological interventions has been explored as an analgesic strategy in great depth.
How does nociceptive information in the dorsal horn reach higher centres in the brain?
The output from the dorsal horn to higher centres in the brain is carried by spinal projection neurones along ascending pathways. A large population of projection neurones is found superficially in lamina I. It is estimated that 80% of these cells express the neurokinin 1 (NK1) receptor for substance P. NK1-positive cells in lamina I have been shown to project to areas in the brain such as the thalamus, the periaqueductal grey (PAG), and in particular the parabrachial area (PB). In addition to transmitting pain signals up to higher centres in the brain, these cells also project into brainstem areas such as the rostral ventromedial medulla (RVM), a region which has descending projections back to the dorsal horn. Therefore, lamina I NK1-expressing cells can modulate spinal processing by activation of descending pathways from the brainstem.
A large number of projection neurones are also found deeper in the dorsal horn from lamina III–VI and these project predominantly to the thalamus, thereby making up a significant proportion of the spinothalamic tract. This ascending pathway carries primarily sensory information and so provides the sensory component of the pain experience.
Nociceptive infomation from the dorsal horn to the thalamus then goes where?
From the thalamus, nociceptive information is transmitted to cortical regions. There does not exist a single pain centre within the cortex, but rather there are various cortical regions which may or may not be activated during a particular painful experience. These regions make up what is commonly referred to as a ‘pain matrix’ and include primary and secondary somatosensory, insular, anterior cingulate, and prefrontal cortices.
What do nociceptive stimuli evoke?
Painful stimuli evoke not only discrete sensory perceptions and somatic motor responses but also marked changes in emotional and autonomic states.
How is nociceptive information carried from the periphery to the spinal cord? (Talk about both superficial and deep laminae)
From the periphery to the spinal cord, nociceptive messages are primarily conveyed by Ad- and C-fibres. These nociceptive primary afferents enter the CNS via the dorsal roots and terminate mainly in the superficial laminae (I + II) of the dorsal horn although they also send collateral projections to deep laminae (V + VI + adjacent VII + X) of the dorsal horn (Willis & Coggeshall, 1991). Furthermore, the tactile (Ab) fibres that target the intermediate (III+IV) laminae, spare the superficial laminae whereas they send collateral projections to deep laminae. Such an anatomical organisation indicates that two regions of the dorsal horn, the superficial and the deep laminae, are involved in nociceptive processing. This organisation explains why superficial laminae contain chiefly nociceptive-specific neurones (i.e. activated only by noxious inputs) whereas deep laminae contain rather wide dynamic range neurones (i.e. activated by noxious and tactile inputs).
Where do neurons of the deep lamina (Lamina V) project to? As a result how do these contribute to the pain experience?
These neurons have a minimal contribution to the spino-thalamic tract. Bernard et al., (1995) used anterograde tracers to identify a dense projection from the deep laminae to caudal reticular nuclei. These include the lateral reticular nucleus (LRD) and the subnucleus reticularis dorsalis (SRD), amongst others. These areas are known as “motor” reticular areas and so it is likely that this system may also make an important contribution to the genesis of motor reaction/reflex response induced by noxious stimuli. Furthermore, because the SRD projects back to nociceptive deep laminae, this system could also modulate the transmission of nociceptive messages (Almeida et al. 1999).
In addition the deep laminae also projects to the the parabrachial internal lateral sub nucleus (PBil).The PBil neurones exhibit strong ‘wind up’ and long-lasting after- discharge in response to noxious stimuli. Furthemore these neurons project to the medial thalamic areas linked to the striato-cortical prefrontal compartment. As such, this system could deal with attention and motivational aspects of pain through a general arousal of the prefrontal pole of the brain.
Why is lamina 1 so important in pain signalling?
From the periphery to the spinal cord, nociceptive messages are primarily conveyed by Ad- and C-fibres, which terminate mainly in the superficial laminae (I + II) of the dorsal horn. Lamina I neurones constitute the main output of this superficial layer. Furthermore, the cutaneous receptive fields of lamina I neurones are often very restricted, making them suitable for signalling localised pain.
What areas do lamina 1 neurons project to? How does this contribute to the pain experience?
One extensive projection is to the ventral posterolateral nucleus (VPL) and the ventral posteromedial nucleus (VPM). This thalamic area also recieves a tactile input from dorsal column neurones, and projects to the primary somatosensory cortex. As a result, it is likely that this system is involved in the discriminative aspect of nociceptive processing.
Another extensive projection from lamina 1 is to the parabrachial nucelus (known as the “house alarm”). Gauriau and Bernard (2002) used an anterograde tracer and identified that the nociceptive portion of the PB area has two main targets in the forebrain, the amygdala and the hypothalamus, and two significant targets in the brainstem, the periaqueductal grey matter and the ventrolateral medulla.
How do lamina 1 projections to the amydala contribute to the pain experience?
In the amygdala, the ‘nociceptive’ projections from the PB area target primarily the lateral capsular division (CeLC) and to a lesser extent the lateral division (CeL) of the central nucleus (Bernard et al. 1993; Jasmin et al. 1997).
The amydala also sends projections to the bed nucleus of the stria terminalis (BNST), which is sometimes reffered to as the extended amydala. These areas are likely to contribute to specific components of aversive emotions, for example, the anxiety, the fear-evoked avoidance learning, the anti- nociception and the autonomic adjustments that occur in the face of dangerous or painful situations As a result, activation of the PB–amygdaloid connection by noxious inputs could be the link through which pain-related emotional reactions are triggered.
How do lamina 1 projections to the ventromedial hypothalamus and the Periaqueductal grey (PAG) contribute to the pain experience?
These areas are thought to play an important role in motivational behaviour such as defense, aggression and flight. An additional role in the homeostatic regulation of energy metabolism (disruption of feeding and catabolism of brown fat) in response to pain may be envisaged (Malick et al. 2001).
In the periaqueductal grey, the ‘nociceptive’ projections from the PB area terminate in the ventrolateral, lateral and dorsomedial columns. The ventrolateral column is involved in passive emotional coping strategies (quiescence, immobility and hyporeactivity). The lateral column is involved in active emotional coping strategies, characterised by an engagement with the environment (confrontation, fight and flight). The dorsomedial column, although much less studied, seems to be involved in strongly aversive (and even ‘explosive’) behaviours.
