Crossing the Pain Barrier: P2 Receptors as Targets for Novel Analgesics

Abstract

In 1995 the P2X 3 receptor was found to be expressed at high levels in nociceptive sensory neurones, consistent with earlier reports that ATP induced pain in humans and animals. At first it was thought that ATP was most likely to play a role in acute pain, following its release from damaged or stressed cells and since then a wide variety of experimental techniques and approaches have been used to study this possibility. Whilst it is clear that exogenous and endogenous ATP can indeed acutely stimulate sensory neurones, more recent reports using gene knockout and antisense oligonucleotide technologies, and a novel, selective P2X 3 antagonist, A-317491, all indicate that ATP and P2X 3 receptors are more likely to be involved in chronic pain conditions, particularly chronic inflammatory and neuropathic pain. These reports indicate that P2X 3 receptors on sensory nerves may be tonically activated by ATP released from nearby damaged or stressed cells, or perhaps from the sensory nerves themselves. This signal, when transmitted to the CNS, will be perceived consciously as chronic pain. In addition, it is now clear that several subtypes of P2Y receptor are also expressed in sensory neurones. Although their distribution and functions have not been as widely studied as P2X receptors, the effects that they mediate indicate that they might also be considered as therapeutic targets in the treatment of pain. Although our ability to treat persistent painful conditions, such as chronic inflammatory and neuropathic pain, has improved in recent years, these conditions are often resistant to currently available therapies, such as opioids or non-steroidal antiinflammatory drugs. This reflects a limited understanding of the underlying pathophysiology. It is now clear that the development and maintenance of chronic pain are mediated by multiple factors, but many of these factors, and the receptors and mechanisms through which they act, remain to be identified. Chronic pain is debilitating and can greatly decrease quality of life, not just due to the pain per se, but also because of the depression that can often ensue. Thus a greater understanding of the mechanisms that underlie chronic pain will help identify new targets for novel analgesics, which will be of great therapeutic benefit to many people.

The effect of serotonin–noradrenaline reuptake inhibitor duloxetine on the intervertebral disk-related radiculopathy in rats

“…Apart from its common antidepressant effect, paroxetine regulate P2X 4 receptor function [30]. The P2X 4 receptor is a ligand-gated ion channel receptor, activated by ATP after nerve injury [7,19,20]. Its expression increases in the ipsilateral spinal cord in hyperactive microglia and its activation is necessary for tactile allodynia [47].…”

The effect of selective serotonin reuptake inhibitor (SSRI) on pain-related behavior in a rat model of neuropathic pain

“…The P2X4 receptor is a ligand-gated ionchannel receptor that is activated by ATP [5,20,21]. The cells expressing P2X4 receptors are microglia, rather than neurons or astrocytes.…”

P2 Receptors Activated by Uracil Nucleotides - An Update

“…The progress in this field has been thoroughly reviewed [124][125][126][127][128][129]. The interest in pyrimidinergic receptors as drug targets is documented by the many patents filed on UTP and UTP derivatives and analogs and other structural classes interacting with pyrimidinergic P2Y receptors as novel therapeutic agents [79,[130][131][132][133][134].…”