Investigations into central mechanisms of pain transmission

Price, Jill (2001) Investigations into central mechanisms of pain transmission. PhD thesis, University of Glasgow.

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The pain transmission system is inherently plastic in nature; plasticity of nociceptive
processing in the dorsal hom of the spinal cord is believed to contribute to clinical states of
post-injury pain hypersensitivity. Both enhancement and tachyphylaxis of nociceptive
processing have been reported previously following repeated carrageenan-induced
inflammation. The present study aimed to investigate central mechanisms involved in the
transformation of pain transmission from 'physiological' to 'pathophysiological' in adult
rats, using a model of mild intraplantar inflammation induced by intraplantar
administration of carrageenan at doses markedly lower than those standardly used in
research into central mechanisms of inflammatory pain transmission. Changes in plantar
inflammation, thermal and mechanical sensitivity were assessed following intraplantar
injection of repeated doses of carrageenan (0.5%, corresponding to a dose of 0.25 mg and
0.1 %, corresponding to a dose of 0.05 mg), administered at weekly (0.5% and 0.1 %) and
daily (0.1%) intervals. Expression of mRNA of key genes implicated in plasticity of
central spinal pain transmission in laminae I, II and V of the dorsal hom of the lumbar
spinal cord (laminae involved in central nociceptive transmission) was investigated using
in-situ hybridisation techniques. The genes investigated were calcium calmodulin kinase
IIa (CaMKIla), a key intracellular molecule instantaneously activated by neuronal
stimulation; alterations in CaMKIla expression can rapidly induce nociceptive plasticity
through modulation of many excitatory and inhibitory nociceptive mediators; the cyclooxygenase
enzymes COX-1 and COX-2, which catalyse prostaglandin synthesis and are
implicated in the modulation of the central nociceptive response to inflammatory injury;
the immediate early genes zif11268, junD and tissue plasminogen activator (tPA), which
have been implicated in the induction and maintenance of neuronal plasticity in higher
centres, and the precursors for the inhibitory neurotransmitter molecules y-amino butyric
acid (GABA), enkephalin and dynorphin. A method for organotypic culture of neonatal
spinal cord was developed and characterised with the aim of providing a useful technique
for more detailed study of the molecular basis of nociceptive plasticity.
Mild inflammatory injury induced by 0.5% and 0.1% carrageenan treatment induced
consistent hyperalgesic behaviour, which did not change following weekly repeated injection. Temporary attenuation of hyperalgesia developed following daily repetitive
administration of 0.1 % carrageenan, but hyperalgesia returned when this repetitive
inflammatory stimulation was maintained. Preliminary studies on the role of NMDA
receptors, opioid receptors and a 2A adrenoreceptors in the mediation of this tachyphylaxis
suggest that these receptor systems did not playa major role in the observed tachyphylaxis
In-situ hybridization studies did not identify changes in gene expression induced by
repetitive carrageenan treatment in lamina V. In laminae I1II, changes were observed in
expression of certain genes (notably CaMKIla, COX-2 and proenkephalin), but not of
immediate early genes, GAD 67 or prodynorphin. Hyperalgesia associated with weekly
carrageenan treatment correlated closely with significantly enhanced transcription of
CaMKIla mRNA in laminae IIII; moreover, tachyphylaxis of hyperalgesic behaviour
correlated with attenuation of CaMKIla upregulation. Since increased expression of
CaMKIla, leading to regulation of expression of a range of kinase-dependent receptors and
intracellular mediators, is a hallmark of neuronal plasticity in higher centers, this suggests
that central plasticity of nociceptive transmission in the dorsal hom could have contributed
to the development of hyperalgesia following carrageenan treatment. Weekly
administration of carrageenan also consistently induced significant upregulation of COX-2
and proenkephalin mRNA expression in laminae I1II, suggesting that ultimate modulation
of pain sensation following inflammatory injury is determined by the interaction of
excitatory and inhibitory transmitter pathways. COX-I, prodynorphin and GAD 67 mRNA
expression were not significantly changed in relation to the intensity of inflammatory
injury or in relation to changes in nociceptive responses. This would suggest that these
mediators did not play a key role in the modulation of spinal nociceptive transmission
associated with mild inflammatory injury. With the possible exception of CaMKIla,
changes in gene expression did not correlate closely with plasticity of nociceptive
behaviour induced by daily repeated carrageenan treatment.
200 !lm transverse slices of postnatal spinal cord were cultured successfully for up to 5
days using a simple interface culture system. Histochemical and immunocytochemical
assays indicated that the architecture of organotypically cultured spinal cord closely
resembled that observed in-vivo.
This study presents a new approach to the investigation of neuronal plasticity associated
with tissue injury and inflammation. Different mechanisms underlying plasticity of nociceptive responses may be induced by induced by high intensity as opposed to lowintensity
injury. The observation of tachyphylaxis of hyperalgesia following daily repeated
carrageenan treatment may represent engagement of endogenous 'anti-hyperalgesic'
mechanisms. Further investigation of the molecular basis of endogenous 'antihyperalgesia',
facilitated by organotypic slice culture techniques, may identify new targets
for the treatment and prevention of persistent pathological nociceptive transmission
following inflammatory injury.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: S Agriculture > SF Animal culture > SF600 Veterinary Medicine
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
Supervisor's Name: Nolan, Professor Andrea and Morris, Dr. Brian
Date of Award: 2001
Depositing User: Mrs Marie Cairney
Unique ID: glathesis:2001-4812
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 09 Jan 2014 11:32
Last Modified: 09 Jan 2014 15:39

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