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Title: The role of NK1 and NK2 neurokinin receptors in the acute and sustained nociceptive activation of dorsal horn neurons
Author: Munro, Fiona E.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1997
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The tachykinins substance P (SP) and neurokinin A (NKA) can be released from fine somatosensory afferents into the spinal cord by noxious cutaneous stimuli. This study assessed the role of their respective NK1 and NK2 receptors and some putative intracellular mediators in both acute and sustained nociceptive inputs to dorsal horn neurons: (a) In anaesthetised rats, extracellular recordings were made from laminae III-V multireceptive neurons. The ionophoretic administration of NK1 antagonists L-668,169, GR 82334 and [D-Pro4,D-Trp7,9,10Phe11]substance P-(4-11) failed to influence neuronal responses to noxious pinch or heat, but often enhanced responses to innocuous brush, whilst the NK2 antagonist L-659,874 inhibited responses to noxious heat, but not pinch or brush. Selective NK1 and NK2 receptor agonists, [N-acetyl-Arg6,Sar9,Met(O2)11]SP6-11 and GR 64349 respectively, both excited dorsal horn neurons. The contribution of NK1 and NK2 receptors to sustained neuronal activity induced by peripheral application of the C-fibre selective algogen mustard oil was then investigated. (b) Evidence for a role of protein kinase C (PKC) in mediating sustained nociceptive responses of rat horn neurons was provided by the blockade of mustard oil-, but not brush-evoked neuronal activation by the PKC inhibitors GF 109203X and chelerythrine and by SR 48968-sensitive subcellular translocation of [3H]phorbol 12,13-dibutyrate binding sites ipsilateral to mustard oil stimulation. (c) In situ hybridisation histochemistry (ISSH) demonstrated that expression of c-fos mRNA, induced in the superficial dorsal horn by peripheral application of mustard oil was inhibited by systemic administration of both RP 67580 and SR 48968. (d) The effects of intrathecally-applied NK1 and NK2 antagonists were assessed on thermally-evoked tail-flick and paw-flick behavioural responses. GR 82334 and L-659,874 had no effect alone, but in combination inhibited paw-flick. After inflammation induced by intraplantar injection of carrageenan, each was effective individually. These results provide evidence that spinal NK2 receptors are involved in mediating both acute and sustained nociceptive transmission, probably acting through phosphoinositide hydrolysis and stimulation of protein kinase C(PKC). However, evidence for NK1 receptor involvement was only obtained in sustained or inflammatory models of nociceptive transmission in the spinal dorsal horn.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available