Pain is a fundamental experience characterized by an unpleasant physical perception and corresponding emotional state.
Disease or trauma affecting the peripheral or central neuronal sensory pathway can produce a form of chronic pain known as
neuropathic pain. This pain may occur with central nervous system disorders, such as stroke or multiple sclerosis, or with
conditions associated with peripheral nerve damage, such as diabetic neuropathy or viral infection. It can also be induced by
mechanical trauma or by neurotoxic chemicals (for example, chemotherapeutics). The control of pain has been a major goal of
pharmacotherapy from the earliest times; however, effective management of both acute and chronic pain remains suboptimal.
The situation is particularly challenging for chronic pain and neuropathic pain sufferers, for which there is a high unmet need.
Indeed, it is estimated that only one in four patients experience over 50% pain relief .
One of the major reasons why pain relief remains such a challenge is the robust inter-individual variability that exists in
sensitivity to pain and the response to analgesics . Much of the variability in chronic pain and analgesic response is heritable,
yet an understanding of the genetic determinants underlying this variability is far from complete. In a study just published by
Sorge and colleagues (2012), the authors show that variation within the coding sequence of the gene encoding the P2X7
receptor (P2X7R) affects chronic pain sensitivity in both mice and humans. P2X receptors function as ATP-gated nonselective
ion channels permeable to Na+, K+, and Ca2+. The P2X7R is rather unusual among the P2X receptor family in that sustained
activation by extracellular ATP causes the formation of a reversible plasma membrane pore permeable to molecules with a
mass of up to 900 Da . Specifically these authors made use of genome-wide linkage analyses to identify an association
between nerve-injury-induced pain behavior (mechanical allodynia) and the P451L mutation of the mouse P2rx7R gene. Mice
bearing P2X7Rs having impaired pore formation showed less allodynia than mice with the pore-forming P2rx7 allele.
Administration of a peptide corresponding to the P2X7R C-terminal domain, which blocked pore formation but not cation
channel activity, selectively reduced nerve injury and inflammatory allodynia only in mice with the pore-forming P2rx7 allele.
Importantly, in independent human chronic pain cohorts (mastectomy and osteoarthritis), a genetic association between lower
pain intensity and the hypofunctional His270 (rs7958311) allele of P2X7R was observed.
Currently available drugs for neuropathic pain include antidepressants, anticonvulsants, sodium channel blockers, N-methyl-Daspartate
receptor antagonists, and opioids. Unfortunately, these drugs were designed to hit neuronal targets and focus on
blocking neurotransmission. They can treat pain symptoms but not the underlying pathology of neuropathic pain. Further, they
only provide a transient relief of neuropathic pain in only a fraction of patients and produce severe CNS side effects. From their
findings, Sorge et al. (2012) posit that selectively targeting P2X7R pore formation while leaving cation channel activity intact
could provide a preferred strategy for reducing pain in individuals who carry P2X7R haplotypes that confer a high risk for