PURINES IN PAIN MECHANISMS: NEW
INSIGHTS
The
purine nucleoside adenosine and its phosphorylated derivatives AMP, ADP and ATP,
have been accorded full status as neurotransmitters.
The
transmitter activity of purine nucleosides and nucleotides was first recognised
at the periphery. It was shown that externally applied ATP caused vasodilation,
especially coronary vasodilation. Later it was shown that the nerve plexus of
the gastro-intestinal tract contained many non-adrenergic, non-cholinergic
fibres (NANC). The transmitter used by these NANC neurons turned out to be ATP,
so it was proposed that these axons should be re-christened purinergic fibres.
Then purinergic receptors were identified on the presynaptic membrane of the
neuromuscular junction where release of adenine nucleotides reduced the release
of ACh. Similarly, it was found that adenine nucleotides reduced the release of
noradrenaline from adrenergic terminals.
Purine
transmitters are now known to be associated with many cerebral systems and to
be widely involved in cerebral physiology.
Purine
receptors are divided into two large classes: P1 receptors sensitive to
adenosine and AMP, and P2 receptors sensitive to ADP and ATP. Both classes are
further subdivided into subclasses. It has been found that whilst the members
of one subclass of P2 receptor, the P2Y receptors, are metabotropic, the
members of the other subclass, the P2X receptors, are ionotropic.
There
are at least seven and probably more different P2X subunits varying from 388 to
595 aminoacids in length. The P2X structure makes only two passes through the
membrane, like mechanosensitive channels of hair cells and epithelial Sodium channels.
The
P2Y metabotropic receptors show the canonical 7TM conformation of other
G-linked proteins.
Liu
& Salter have recently reviewed the role of purine receptors in pain
mechanisms, outlining a general sketch of
the research in the field and showing some new insights (Purines and pain mechanisms: recent developments. Curr. Opin. Investig.
Drug 6, 65-75, 2005).
Single
P2 subtypes are specifically involved in different features of pain processing.
P2X3, found in primary sensory neurons, is the most studied subtype for its involvement
in inflammatory and neuropathic pain. Accordingly, in animal models of
inflammatory and neuropathic pain, it has been demonstrated that the inhibition
of P2X3 subtype can reduce pain-related behaviours.
P2X
receptors have been implicated in pain hypersensitivity subsequent to nerve
injury. It is interesting that a growing body of evidence shows a role for
metabotropic P2Y and P2Y2 receptors in pain hypersensitivity.