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VOL. 71 (2), 283-319, 2005 PURINERGIC SIGNALLING: THERAPEUTIC POTENTIAL
Intracarotid administration of ATP, selectively increases blood
flow in transplanted, malignant gliomas and suggests that this might
enhance the delivery of anti-cancer agents to malignant brain
tumours.
PAIN
The involvement of ATP in the initiation of pain was recognised
early, by Collier et al. in 1966 and Bleehan & Keele in 1977. A major
advance was made when the P2X3 ionotropic receptor was cloned in
1995 and shown to be localised predominantly in the subpopulation
of small nociceptive sensory nerves that label with isolectin IB4 in
dorsal root ganglia. Later, Burnstock (31) put forward a unifying
purinergic hypothesis for the initiation of pain associated with
causalgia, reflex sympathetic dystrophy, angina, migraine and cancer
pain, which has been followed by an increasing number of papers
expanding on this concept for acute, inflammatory, neuropathic and
visceral pain. Sensory terminals are sensitive to ATP and a, ß-
methylene ATP in the tongue, tooth pulp, bladder (32), ureter (33)
and gut (10). Both P2X3 (homomultimer) and P2X2/3 (heteromultimer)
receptors mediate nociceptive afferent responses, but the proportions
vary in different organs. P2Y receptors have also been demonstrated
in a subpopulation of sensory neurons which colocalise with P2X3
receptors.
The search is on for selective P2X3 and P2X2/3 receptor antagonists
that do not degrade in vivo. PPADS is a non-selective P2 antagonist,
but has the advantage that it dissociates about 100-10,000 times
more slowly than other known antagonists. The trinitrophenyl-
substituted nucleotide, TNP-ATP, is selective and very potent at
both P2X3 and P2X2/3 receptors. A-317491 is a potent and selective
non-nucleotide antagonist of P2X3 and P2X2/3 receptors and it
reduces chronic inflammatory and neuropathic pain in the rat (34).
Antisense oligonucleotides have been used to downregulate the P2X3
receptor and in models of neuropathic (partial sciatic nerve ligation)
and inflammatory (complete Freund’s adjuvant) pain, inhibition of
the development of mechanical hyperalgesia as well as significant
reversal of established hyperalgesia, were observed within 2 days of
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