On the Role of ATP-Gated P2X Receptors in Acute, Inflammatory and Neuropathic Pain

The somatosensory system is the part of the nervous system that has evolved to integrate sensory input signals from the body including touch, heat and pain sensations. The primary afferent neurons, located on the dorsal side of the spinal cord, dorsal root ganglion (DRG) neurons are pseudomonopolar neurons that conduct sensory information encoded by the frequency of action potentials along their processes from the peripheral sites (e.g. skin) to the dorsal horn of the spinal cord. Broadly speaking, there are two different types of pain: acute and chronic. Acute pain, also called nociceptive pain, is a sensation experienced in response to injury or tissue damage (Millan 1999). The relatively short duration of such pain acts as a signal to warn the subject about an imminent danger (e.g. stepping on a sharp object like a pin). This type of pain is conducted through nociceptor myelinated A-delta and unmyelinated C-fiber neurons classified depending on their myelination status (Snider and McMahon 1998). In contrast, chronic pain has no “warning” function for the subject and is usually the manifestation of an underlying injury, disorder or disease this type of pain can last for several years. Chronic pain is subclassified into neuropathic pain and inflammatory pain. Neuropathic pain is due to damaged or misfiring peripheral nerves, whereas inflammatory pain is derived from a non-specific immune response that alters nerve function. Understanding the cellular and molecular basis of pain has been a stated goal of biological research for several decades accounting for increased recent interest in extracellular ATP signaling. Adenosine, 5’-triphosphate (ATP) is a ubiquitous molecule found in every cell in the millimolar concentration range and released into the extracellular milieu after tissue injury or visceral distension once released activates ATP receptor molecules on nearby sensory nerves. Extracellular ATP is an endogenous agonist at P2 purinoceptors, which comprise metabotropic G proteincoupled P2Y receptors and ionotropic cation-permeable P2X receptors (Ralevic and Burnstock 1998). To date, seven P2X subunits have been cloned. They share a common topology displaying two transmembrane domains linked by a large extracellular loop and intracellular N- and C-terminal tails (North 2002). Their activation by ATP induces the opening of a pore permeable to Na, K and Ca, inducing an overall depolarization of the cell (Khakh and North 2006). From the perspective of human medicine, a role for ATP signaling in pain has its roots in pioneering studies carried out several decades ago. In 1966, Collier and colleagues, followed 10 years later by Bleehen and Keele, showed that local application of ATP onto human skin blisters induced a persistent sensation of pain (Bleehen and Keele 1977; Collier et al. 1966). These papers instigated subsequent studies where a role for ATP as an extracellular chemical messenger that transmits sensory information has been investigated in humans and animals. A boost to the field has derived from the use of genetic methods such as knockout mice and antisense oligonucleotides, as well as the availability of P2X receptor specific antagonists. Using such approaches, the involvement of ATP-activated receptors has been related to different types of pain (Table 10.1). The latest data suggest that whereas acute pain seems to be linked to the activation of P2X3 receptors expressed in sensory neurons, neuropathic pain more likely involves P2X4 receptors on the surfaces of glial cells, and inflammatory pain involves P2X7 receptors on immune cells.