The bilaterally to the lateral parabrachial nucleus


The branches of the pruriceptive fibres terminate in the
spinal or medullary dorsal horn and activate second order neurones. Important
neurotransmitters released from the pruriceptive fibres include glutamate,
substance P, gastrin-releasing peptide (GRP) and brain natriuretic peptide
(BNP). Current data suggest that there exists a complex spinal itch-signalling
pathway in which the BNP released from pruriceptors stimulates the release of
GRP and then substance P, which in turn acts on neurokinin 1 (NK1) receptors,
the ablation of which has been shown to reduce itch. Almost all spinal neurones
terminating in the thalamus and parabrachial nucleus express NK1 receptors. It
has been shown that antagonists for NK1, GRP and glutamate receptors inhibited
scratching behaviour. In terms of the ascending rout of the pruriceptive
stimulus, the pruriceptive afferents project to the contralateral ventrobasal
thalamus and bilaterally to the lateral parabrachial nucleus via the
Spinothalamic and spinoparabrachial tracts respectively. In terms of the
distinction between pain and itch, it must be noted that most
pruritogen-resposive neurones are also stimulated by other pain-inducing
stimuli such as capsaicin and mustard oil. However, it has been hypothesised
and supported by animal studies that itch-signalling neurones also transmit
pain, whereas pain is transferred by nociceptive afferents that do not respond
to itch.  When looking at skin burn
inducing either pain or itch, it has been noted that when the burn is almost
healed or located superficially in the skin, itch predominates, whilst pain is
induced upon damage to deeper cutaneous levels (Meng).

Given that scratching is known to stop itch, the
mechanisms underlying this process also need attention. Interestingly,
scratching does not inhibit algogen-induced itch. The main mediators in scratch
inhibition are GABA and glycine, with the removal of spinal glycine was shown
to induce excessive scratching. Moreover, another key player in itch inhibition
is the class of inhibitory inter-neurones expressing Bhlhb5, as has been shown in studies whereby
these inter-neurones were ablated, with resulting increased itch behaviour. These
inter-neurones are thought to release dynorphin, which activates the kappa
opioid receptors. The kappa opioid antagonist nalfurafine has been shown to
reduce itch behaviour in mice and also reduce the itch of chronic kidney
disease in human subjects. Furthermore, mice lacking Bhlhb5 had increased
pruritic responses, which improved after spinal transplantation of GABA-ergic
neurones. These findings highlighted above show the role of GABA, glycine and
dynorphin in the spinal modulation of itch. 

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