Project 12:
Supervisor:
Investigating the Role of Peroxisome Proliferator-Activated
Receptors in Endogenous Analgesia
Dr. David P. Finn, Department of Pharmacology and Therapeutics
Project Summary: The overall objective of Dr. Finn’s research is to increase
understanding of the neurobiological mechanisms underlying the development and
treatment of pain, inflammation, mood disorders and impaired cognition. His work is
concerned with elucidating the role of a number of different receptor types
(cannabinoid, opioid, adrenoceptor, imidazoline, serotonin, vanilloid, N-type Ca 2
channels) in mediating and modulating behavioural, neurochemical and
neuroendocrine responses relevant to pain, anxiety, depression and cognition. A
detailed understanding of the physiology of nociception and the endogenous analgesic
system is essential for the development of new therapies to treat pain. Induction of
fear-induced analgesia (FIA) in rodents is an excellent model to study the physiology
of endogenous analgesic and aversive systems because FIA models the analgesia
which is expressed upon exposure to stimuli associated with learned danger/fear. FIA
can be profound, reducing nociceptive behaviour in rodents by as much as 90% 2.
Thus, increased understanding of the molecular mediators of FIA is of physiological
and potential therapeutic significance.
Several neurotransmitter systems are known to mediate FIA including the
endogenous opioid, monoaminergic and GABAergic systems3. His work has
suggested that endogenous cannabinoids may act through CB1 and CB2 receptors to
mediate FIA2,4. However, recently endocannabinoids have been shown to act through
non-CB1/non-CB2 receptor-dependent mechanisms and nuclear peroxisome
proliferator-activated receptors (PPARs), particularly PPAR-α and PPAR-, have
emerged as novel endocannabinoids targets5. Moreover, recent work has shown that
PPARs may mediate the analgesic effects of endocannabinoids6. However, the role of
PPARs in FIA has not been investigated. The aim of the present study is to
investigate the effects of pharmacological antagonism of PPAR-α or PPAR- on
expression of FIA in rats.
The student will study the effects of acute, systemic (i.p.) administration of the
PPAR-α and PPAR- antagonists on FIA in rats and will be assessed using models and
methodology identical to that described previously2,4. All experimental procedures on
living rats will be carried out under licence from the Department of Health and
Children in accordance with the Cruelty to Animals Act, 1876 (SI 17/94) and EU
Directive 86/609 and following approval by the Animal Care and Research Ethics
Committee at NUI, Galway.
The student will work closely with a post-doctoral researcher and will be involved in
all aspects of the study from experimental design and execution to data analysis and
presentation.
Specifically, they will gain expertise in behavioural
neuropharmacology, animal husbandry, computer-assisted assessment of rodent painand anxiety-related behaviour, statistical analysis and oral and written presentation of
data. They will be fully integrated into the research team for the duration of the
project. The full repertoire of expertise and facilities in Dr Finn’s research group/lab
will be at the student’s disposal and they will benefit from intensive exposure to the
integrative whole-systems neuroscience approach employed in the lab.
References: [1]. Loeser and Melzack,(1999) Lancet 353, 1607-1609; [2]. Finn, et al.
(2004). Eur J Neurosci 20, 848-852.; [3] Ford and Finn (In Press) Pain.; [4] Butler et
al. (In Press) Pain.; [5] O'Sullivan, SE (2007) Br J Pharmacol 152 (5): 576-582.; [6].
Sagar et al. (2008). Br J Pharmacol. [Epub ahead of print].