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.