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PERSPECTIVES IN PHARMACOLOGY

Painful Purinergic Receptors

Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois

Received for publication August 16, 2007
Accepted November 21, 2007.

	Abstract

Top Abstract P2X3 and P2X2/3 Receptors P2X4 Receptors P2X7 Receptors P2Y Receptors Perspective References

 
Multiple P2 receptor-mediated mechanisms exist by which ATP can alter nociceptive sensitivity following tissue injury. Evidence from a variety of experimental strategies, including genetic disruption studies and the development of selective antagonists, has indicated that the activation of P2X receptor subtypes, including P2X₃, P2X_2/3, P2X₄ and P2X₇, and P2Y (e.g., P2Y₂) receptors, can modulate pain. For example, administration of a selective P2X₃ antagonist, A-317491, has been shown to effectively block both hyperalgesia and allodynia in different animal models of pathological pain. Intrathecally delivered antisense oligonucleotides targeting P2X₄ receptors decrease tactile allodynia following nerve injury. Selective antagonists for the P2X₇ receptor also reduce sensitization in animal models of inflammatory and neuropathic pain, providing evidence that purinergic glial-neural interactions are important modulators of noxious sensory neurotransmission. Furthermore, activation of P2Y₂ receptors leads to sensitization of polymodal transient receptor potential-1 receptors. Thus, ATP acting at multiple purinergic receptors, either directly on neurons (e.g., P2X₃, P2X_2/3, and P2Y receptors) or indirectly through neural-glial cell interactions (P2X₄ and P2X₇ receptors), alters nociceptive sensitivity. The development of selective antagonists for some of these P2 receptors has greatly aided investigations into the nociceptive role of ATP. This perspective highlights some of the recent advances to identify selective P2 receptor ligands, which has enhanced the investigation of ATP-related modulation of pain sensitivity.

The ability of ATP (Fig. 1) to modulate neural function has been well documented (Burnstock and Williams, 2000; Burnstock, 2007). Mechanistic understanding of the role for ATP in processing painful sensory information was initially indicated by early demonstrations that ATP was released from sensory nerves (Holton and Holton, 1954; Holton, 1959) and by subsequent data showing that ATP produces fast excitatory action potentials in dorsal root ganglionic (DRG) neurons (Jahr and Jessel, 1983). Whereas the inhibitory effects of adenosine (ADO) and direct acting ADO receptor agonists on nociceptive neurotransmission and nocifensive behavior have been generally accepted (McGaraughty and Jarvis, 2006; Sawynok, 2007), the specific mechanisms by which ATP serves to modulate neuronal function remained ambiguous until the discovery of distinct adenosine-sensitive P1 and ATP-sensitive P2 receptor classes, which allowed for initial investigations of the pharmacology of the individual receptor subtypes (Burnstock, 2007). It is now known that ATP receptor superfamilies comprise both G-protein coupled receptors (P1 and P2Y receptors) and ligand-gated ion channels (P2X receptors) (North, 2002; Burnstock, 2007).

View larger version (14K): [in this window] [in a new window]   Fig. 1. Structures of prototypical P2 receptor agonists.

P2X receptors function as nonselective cation channels (permeable to Ca²⁺, Na⁺, and K⁺) and are expressed on a variety of excitable cells, including neurons, glia, and smooth muscle cells (North, 2002; Khakh and North, 2006). Stimulation of P2X receptors can also lead to downstream activation of voltage-operated calcium channels and Ca²⁺-stimulated tyrosine kinases that in turn activate mitogen-activated protein kinases (extracellular signal-regulated kinases 1 and 2) to modulate transcriptional processing (Khakh and North, 2006). Extracellular ATP availability arises from a variety of mechanisms, including mechanical stimulation, vesicular release with other neurotransmitters (e.g., acetylcholine, norepinephrine, glutamate, GABA, and neuropeptide Y), or cellular damage (e.g., hypoxia) (Burnstock and Williams, 2000; North, 2002; Burnstock, 2007). Once released, the extracellular actions of ATP are limited by its rapid degradation by membrane-bound and soluble nucleotidases (Burnstock, 2007). The metabolic degradation of ATP leads to increased extracellular levels of ADP, AMP, and ADO, all of which have specific receptor-mediated activities. In the context of nociceptive neurotransmission, activation of P1 receptors by ADO decreases nociception, inflammation, and cellular excitability (McGaraughty and Jarvis, 2006), whereas P2X receptor activation by ATP stimulates cellular excitability, augments the release of excitatory amino acids, initiates nociceptive responses, and can lead to apoptosis (Burnstock and Williams, 2000; Burnstock, 2007). Activation of P2Y receptors also facilitates excitatory neurotransmission by modulating glial-neuron synaptic activity, sensitizing polymodal integrators, such as the transient receptor potential-1 (TRPV1) receptor (Moriyama et al., 2003), and propagating calcium-dependent neuronal activity (Burnstock, 2007).

Historically, a significant limitation in the interpretation of P2 receptor biology has been due to the fact that few, if any, ligands showed meaningful pharmacological selectivity of individual P2 receptor subtypes. Essentially, all of the known P2X receptor agonists have pharmacological activity at multiple P2 receptor subtypes (Jacobson et al., 2002). Furthermore, traditionally used antagonists, such as suramin and PPADS (Fig. 2), are generally weak blockers of P2 receptors and have a multitude of other pharmacological actions (Jacobson et al., 2002; Burnstock, 2007). As discussed below, the discovery of receptor-selective antagonists has helped provide greater clarity as to the specific functional roles of these receptors.

View larger version (16K): [in this window] [in a new window]   Fig. 2. Structures of prototypical and nonselective P2 receptor antagonists.

	P2X3 and P2X2/3 Receptors

Top Abstract P2X3 and P2X2/3 Receptors P2X4 Receptors P2X7 Receptors P2Y Receptors Perspective References

 
Intradermally administered ATP elicits pain in humans under normal conditions and enhances inflammatory-mediated pain (Bleehen and Keele, 1977; Hamilton et al., 2000) by exciting both mechanoresponsive and mechanoinsensitive C-fibers (Hilliges et al., 2002). Experimentally, the nociceptive effects of intradermally administered P2X receptor agonists [e.g., ATP, ,β-methyleneATP (,β-meATP), and BzATP; Fig. 1] are short-lasting (1–10 min) and similar in magnitude compared with that produced in the acute phase of the standard formalin test, a neurogenic inflammatory pain model in rodents (Jarvis et al., 2001). As has been observed in humans, both the potency and effectiveness of locally administered P2X receptor agonists to elicit nociceptive responses are increased in situations of peripheral inflammation-induced neuronal sensitization (Hamilton et al., 2000; Sawynok, 2007). Stimulation of spinal P2X receptors may also contribute to nociception as indicated by the ability of i.t. administered P2X receptor agonists to increase sensitivity to acute and persistent noxious stimuli in rodents (Nakagawa et al., 2007).

P2X receptor antagonists (e.g., suramin and PPADS; Fig. 2) have been demonstrated to reduce nociceptive sensitivity in a wide variety of animal models, including tail-flick, chemically induced persistent and inflammatory pain, and neuropathic pain (Inoue, 2006; Sawynok, 2007). However, their poor selectivity and weak potency has led to conflicting reports of both pronociceptive and antinociceptive effects following P2X receptor blockade (Jarvis, 2003). Interestingly, P2X agonist-induced receptor desensitization may also lead to reduced pain sensitivity following the initial pronociceptive effect (Inoue, 2006). TNP-ATP (Fig. 2) is the most potent P2X₃ receptor antagonist (Jacobson et al., 2002). TNP-ATP has low nanomolar affinity for blocking P2X₃ receptors but also has high affinity for P2X₁ receptors and is rapidly degraded in situ (North, 2002). Thus, in vivo studies of TNP-ATP as a pharmacological tool have been limited to direct intrathecal administration (Jarvis, 2003) or direct administration into a site of peripheral tissue damage (Jarvis et al., 2001; Honore et al., 2002).

Several novel non-nucleotide small molecule P2X₃ antagonists have been reported. A-317491 (Fig. 3) has nanomolar affinity for blocking both P2X₃ and P2X_2/3 receptors and is a competitive antagonist (Jarvis et al., 2002). RO-3 (Fig. 3) is another recently identified antagonist that potently blocks P2X₃ receptors (pIC₅₀ = 7.0) and exhibits at least 100-fold less activity across a wide range of kinases, receptors, and ion channels (Gever et al., 2006). Unlike TNP-ATP, A-317491 is not susceptible to metabolic degradation and shows high systemic bioavailability following subcutaneous administration but lacks oral bioavailability. RO-3 has lower protein binding (48%) compared with A-317491 (99%) and good central nervous system penetration (Gever et al., 2006). Systemic administration of A-317491 effectively reduced nociception in inflammatory and neuropathic pain models (Jarvis et al., 2002). A-317491 also effectively blocked persistent pain in the formalin and acetic acid-induced abdominal constriction tests but was generally inactive in models of acute noxious (thermal, mechanical, and chemical) stimulation. The less active R-enantiomer of A-317491, A-317334, was inactive in animal pain models (Jarvis et al., 2002). RO-3 has also been reported to reduce nociceptive sensitivity in animal pain models (Gever et al., 2006).

View larger version (7K): [in this window] [in a new window]   Fig. 3. Structures of P2X3 receptor-selective antagonists.

	P2X4 Receptors

Top Abstract P2X3 and P2X2/3 Receptors P2X4 Receptors P2X7 Receptors P2Y Receptors Perspective References

 
P2X₄ receptors are widely expressed in a variety of cell types, including both neurons and microglia in the central nervous system (Garcia-Guzman et al., 1997). Homomeric P2X₄ subunits constitute slow desensitizing calcium-permeable cationic channels that can be activated by ATP but are less sensitive to β-meATP and BzATP. P2X₄-mediated currents are relatively insensitive to blockade by suramin or PPADS (IC₅₀ > 500 µM), which inhibit other P2X receptor-related currents in the low micromolar range (Khakh and North, 2006). Unlike other P2X receptors, P2X₄ currents evoked by ATP can be potentiated by ivermectin (Khakh and North, 2006). Coexpression of P2X₄ with P2X₁ (P2X_1/4) or P2X₆ (P2X_4/6) leads to the expression of cationic currents that are pharmacologically distinguishable from homomeric P2X₄-mediated currents (North, 2002). However, it remains to be elucidated whether heteromeric P2X_1/4 and P2X_4/6 receptors form functional channels in native tissues. In a very recent report (Guo et al., 2007), a functional heteromeric combination of P2X₄ and P2X₇ (P2X_4/7) receptors has been described in mouse macrophages.

Recent studies indicate that P2X₄ receptors may play a role in the development of neuropathic and inflammatory pain. P2X₄ mRNA expression has been observed in the DRG, spinal cord, and several regions of the brain (Kim et al., 2003). After spinal nerve injury, P2X₄ receptor protein expression increased in spinal microglia but not in neurons or astrocytes (Inoue, 2006), whereas P2X₄ receptor expression remained unchanged in DRG neurons (Kim et al., 2003). P2X₄ gene knock-down studies have provided further insights into the role of P2X₄ receptors in neuropathic pain. Intrathecal administration of P2X₄ receptor antisense oligodeoxynucleotide decreased P2X₄ receptor expression and suppressed tactile allodynia caused by a peripheral nerve injury (Inoue, 2006). Conversely, intrathecal infusion of ATP-stimulated microglia cells that express P2X₄ receptors produced allodynia in naive rats (Inoue, 2006).

After peripheral nerve injury, a trans-synaptic shift in anion gradient in spinal lamina I neurons, due to the down-regulation of the potassium-chloride exporter, KCC2 (Coull et al., 2003), may transform normally inhibitory anionic synaptic currents to be excitatory, substantially driving up the net excitability of lamina I neurons. This enhanced excitability in spinal cord neurons may play an important role in developing nerve injury-induced pain. Although it is unclear whether P2X₄ receptor signaling is involved in down-regulation of KCC2, recent studies by Coull et al. (2005) revealed that intrathecal injection of P2X₄-activated microglia increased intracellular Cl^– concentrations in lamina I neurons mediated through brain-derived neurotrophic factor and tyrosine kinase receptor B signaling pathways. This shift in the anion reversal potential in lamina I neurons induces neuronal hyperexcitability by means of reducing GABA_A-ergic and glycinergic inhibition (Coull et al., 2005).

The lack of selective P2X₄ antagonists has hindered the pharmacological validation of the role for P2X₄ receptors in pain. Recently, 5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro-[3,2-e]-1,4-diazepin-2-one (Fig. 4) was shown to block P2X₄-mediated currents expressed in Chinese hamster ovary cells with an IC₅₀ value of 0.5 µM (Fischer et al., 2004). It remains to be seen whether novel selective P2X₄ antagonists will elicit analgesic effects in neuropathic and inflammatory pain states.

View larger version (7K): [in this window] [in a new window]   Fig. 4. Structures of P2X4 receptor-selective antagonists.

	P2X7 Receptors

Top Abstract P2X3 and P2X2/3 Receptors P2X4 Receptors P2X7 Receptors P2Y Receptors Perspective References

ATP acting at P2X₇ receptors serves as an efficient secondary stimulus for the maturation and release of IL-1β from proinflammatory cells (Perregaux and Gabel, 1994; MacKenzie et al., 2001; Ferrari et al., 2006). The activation of P2X receptors results in a rapid but reversible channel opening that is permeable to Ca²⁺, Na⁺, and K⁺ ions (North, 2002). P2X₇ receptor-mediated increases in intracellular K⁺ concentrations lead to the activation of caspase-1 and the rapid maturation and release of the proinflammatory cytokine, IL-1β (Perregaux and Gabel, 1994; Solle et al., 2001; Kahlenberg and Dubyak, 2004; DiVirgilio, 2006; Ferrari et al., 2006). P2X ^–/–₇ mice show a disruption in cytokine signaling cascades with perturbation of ATP-induced processing of pro-IL-1β in macrophages (Ferrari et al., 2006). P2X ^–/–₇ mice also show a decreased incidence and severity of arthritis compared with wild-type control mice in a collagen monoclonal antibody-induced model of arthritis (Labasi et al., 2002). Collectively, these data have provided support for the hypothesis that P2X₇ receptor activation may function as a danger signal in the context of tissue trauma and inflammation (Ferrari et al., 2006).

The finding that disruption of P2X₇ receptors not only altered inflammatory pain but also reduced pain associated with frank nerve injury (Chessell et al., 2005) is consistent with the mechanistic role of P2X₇ receptors in modulating IL-1β release and altered pain sensitivity (Wolf et al., 2004). Other genetic manipulations of the IL-1 system, including targeted gene disruption of the IL-1 type I receptor or the IL-1 accessory protein (IL-1acp), as well as transgenic overexpression of the IL-1 receptor antagonist (IL-1ra) (Wolf et al., 2004) or IL-1β double knockout (Honore et al., 2006a), have generated mice that show reduced nociceptive responses relative to wild-type animals.

Early pharmacological work by Dell'Antonio et al. (2002) showed that local administration of oxidized-ATP (Fig. 2) reduces inflammation-induced mechanical hyperalgesia in rats, an effect that is attributed to pharmacological blockade of P2X₇ receptors. However, oxidized-ATP has weak affinity for P2X₇ receptors, slow kinetics, and many other pharmacological actions (Burnstock, 2007). More direct support for a role of P2X₇ receptors in pain modulation is provided by studies using selective antagonists (Honore et al., 2006b; Nelson et al., 2006; McGaraughty et al., 2007). Systemic administration of P2X₇ receptor-selective antagonists (e.g., A-438079 and A-740003; Fig. 5) produced dose-dependent antinociceptive effects in models of neuropathic (Honore et al., 2006b; Nelson et al., 2006; McGaraughty et al., 2007) and inflammatory pain (Honore et al., 2006b). Consistent with their in vitro potencies, A-740003 was more potent than A-438079 at reducing mechanical allodynia 2 weeks after spinal L₅/L₆ nerve ligation. These data illustrate the potential role of P2X₇ receptor modulation in reducing nociception in neuropathic pain models.

View larger version (5K): [in this window] [in a new window]   Fig. 5. Structures of P2X7 receptor selective antagonists.

Using in vivo electrophysiological recording techniques, the antinociceptive action of A-438079 was related to blocking mechanical and thermal inputs to several different classes of spinal neurons (McGaraughty et al., 2007). A-438079 reduced noxious and innocuous-evoked activity of low threshold, nociceptive-specific, and wide dynamic range spinal neurons in neuropathic rats. Spontaneous activity of all classes of spinal neurons was also significantly reduced by A-438079 in neuropathic but not sham rats. The effects of A-438079 on spontaneous and evoked firing were diminished or absent in sham-operated rats. Thus, the contribution of the P2X₇ receptor to spinal nociceptive processing is enhanced after a neuropathic injury and is likely to modulate a diverse spectrum of inputs affecting spinal neuronal excitability.

Studies with P2X₇ receptor-selective ligands provide direct evidence that acute in vivo blockade of P2X₇ receptors significantly reduced nociception in animal models of persistent neuropathic and inflammatory pain (Honore et al., 2006b; McGaraughty et al., 2007). Collectively, these data combined with growing evidence supporting the role of P2X₇ receptor modulation in proinflammatory IL-1 processing (Ferrari et al., 2006) indicate a specific role for P2X₇ receptors in neuralglial cells interactions associated with ongoing pain (Donnelly-Roberts and Jarvis, 2007).

	P2Y Receptors

Top Abstract P2X3 and P2X2/3 Receptors P2X4 Receptors P2X7 Receptors P2Y Receptors Perspective References

 
In comparison to several of the P2X receptors, the contributions of the metabotropic P2Y receptors to normal and pathological pain have been less well examined. As with early P2X receptor research, this area of study is currently lacking selective ligands to interrogate the specific contributions of individual P2Y receptor subtypes in pain states. Eight mammalian P2Y receptors have been cloned (P2Y_{1,2,4,6,11,12,13,14}) that respond in varying degrees to the endogenous ligands ATP, ADP, UTP, and UDP (Fig. 1) (Burnstock, 2007). Tissue localization for P2Y receptors is quite diverse. However, the expression of P2Y₁, P2Y₂, P2Y₄, and P2Y₆ mRNA in DRG neurons suggests that these receptors may be involved in peripheral somatosensory transmission (Moriyama et al., 2003; Burnstock, 2007). In addition to its primary afferent role, there is also some indication that spinal P2Y receptors may modulate pathological nociception (Okada et al., 2002). Of these four P2Y receptors, P2Y₁ and P2Y₂ have garnered the most scientific interest in nociception research. Presently, there is limited evidence to suggest that P2Y₄ and P2Y₆ receptors have active roles in nociception. Indeed, it has been shown that P2Y₆ receptors do not influence the activity of primary afferent C-fibers (Stucky et al., 2004).

P2Y₁ receptor mRNA is up-regulated in the lumbar DRG after peripheral axotomy, indicating that P2Y₁ receptors may contribute to the heightened somatosensory sensitivity in this pathological state (Xiao et al., 2002). More specifically, the P2Y₁ receptor has been localized predominantly to small diameter neurons in the DRG and is coexpressed with P2X₃ and TRPV1 receptors (Gerevich et al., 2004, 2005; Burnstock, 2007). Activation of P2Y₁ receptors on DRG neurons modulates currents generated through N-type (Ca_v2.2) calcium channels and P2X₃ receptors (Gerevich et al., 2004, 2005). Indeed, activation of N-type calcium channels in cultured DRG neurons was inhibited by ATP and even more potently by the P2Y_1,12,13 receptor agonist ADP (Gerevich et al., 2004). The effects of ATP were blocked by the selective P2Y₁ receptor antagonist MRS 2179 (Fig. 6), as well as by PPADS. Likewise, P2Y_1,12,13 receptor agonists inhibited currents evoked by activation of P2X₃ receptors in cultured DRG neurons from neonatal rats (Gerevich et al., 2005). Thus, P2Y₁ may serve as an "ATP counterbalance" following mutual activation of P2Y₁ and P2X₃ receptors. However, in human embryonic kidney 293 cells transfected with P2X₃ receptors, inhibition of P2X₃ currents was reportedly mediated via a P2Y receptor other than P2Y₁ (Gerevich et al., 2007), leaving a putative P2X₃-P2Y₁ interaction in question. Nonetheless, the outcome of P2Y₁-related inhibition on N-type calcium channels or P2X₃ receptors is likely to result in a decreased release of nociceptive transmitters into the spinal cord (Burnstock, 2007).

View larger version (8K): [in this window] [in a new window]   Fig. 6. Structure of the P2Y1 receptor-selective antagonist, MRS 2159.

Early work with TRPV1-transfected human embryonic kidney 293 cells suggested that the P2Y₁ receptor was responsible for the ATP modulation of TRPV1 responses to heat, capsaicin, and protons (Tominaga et al., 2001). More recently, this hypothesis has been revised by proposing that the P2Y₂ receptor is the key purinoceptor involved in the modulation of TRPV1 receptor sensitization (Moriyama et al., 2003). P2Y₂ receptors are expressed on small diameter capsaicin-sensitive DRG neurons (Moriyama et al., 2003; Stucky et al., 2004). Intraplantar injection of ATP reduced thermal thresholds in both wild-type and P2Y₁-deficient mice but not in TRPV1-deficient mice (Moriyama et al., 2003). These results confirmed the link between ATP-induced thermal hyperalgesia and TRPV1 receptors and also demonstrated that P2Y₁ receptors are not necessary for this interaction. Moreover, the P2Y_2,4 receptor agonist, UTP, potentiated capsaicin-evoked currents in isolated mouse DRG neurons and induced thermal hyperalgesia after intraplantar injection (Moriyama et al., 2003). The effect on capsaicin currents was blocked by application of the antagonist suramin, which is somewhat more selective for P2Y₂ over P2Y₄ receptors. Lakshimi and Joshi (2005) also demonstrated that ATP, acting at P2Y₂ receptors, could activate TRPV1 receptors independent of other stimuli or endogenous ligands. Thus, P2Y₂ receptors appear to be the route through which ATP affects TRPV1 function.

The contributions of P2Y₂ receptors for pain transmission probably extend beyond interactions with TRPV1 receptors in primary afferent neurons. In the isolated skin-nerve preparation, 54% cutaneous C-fibers and 12% A-mechanoreceptors responded to UTP (approximately 70–80% were capsaicin-sensitive) (Stucky et al., 2004). However, an additional 22 to 26% of large diameter Aβ fibers responded to UTP, suggesting that P2Y₂ receptors also may be directly involved in the transmission of low-threshold mechanical inputs to the spinal cord. It is also possible that activation of a recently described hetero-oligomeric P2Y₂/ADO A₁ receptor complex (Suzuki et al., 2006) may also negatively modulate the antinociceptive effects of ADO A₁ receptor agonists (McGaraughty and Jarvis, 2006).

	Perspective

Top Abstract P2X3 and P2X2/3 Receptors P2X4 Receptors P2X7 Receptors P2Y Receptors Perspective References

 
Acting via multiple P2 receptor subtypes across the neurotaxis, ATP is an important initiator and modulator of mammalian nociceptive sensitivity. Collectively, the recent discovery of receptor-selective ligands for several of the P2 receptors has provided significant new insights into the mechanisms by which ATP initiates and maintains heightened nociceptive sensitivity in mammals. Based on a series of local delivery (peripheral, spinal, and brain) studies using some of these compounds and an analysis of receptor expression following peripheral nerve injury (McGaraughty and Jarvis, 2006), activation of homomeric P2X₃ receptors probably contributes to acute nociception and some aspects of acute inflammatory pain. In contrast, activation of heteromeric P2X_2/3 receptors appears to modulate longer-lasting nociceptive sensitivity associated with nerve injury or chronic inflammation (Jarvis, 2003; Nakagawa et al., 2007). Furthermore, it is now clear that, under conditions of persistent nociceptive input, activation of other P2 receptors (e.g., P2X₄ and P2X₇) receptors may also serve to maintain nociceptive sensitivity through complex neural-glial cell interactions or via sensitization (via P2Y₂) of other nociceptive receptors such as TRPV1 channels.

Of particular note is the recent report of the existence of natively expressed heteromeric P2X_4/7 receptors (Dubyak, 2007; Guo et al., 2007). This finding provides a potential integrative mechanism of the complex nociceptive roles of both P2X₄ and P2X₇ receptors in chronic pain states. Both receptors share similar sequence homologies, chromosomal localizations, and cellular expression patterns (Dubyak, 2007). As noted above, they also contribute to similar aspects of ongoing inflammatory and neuropathic pain in experimental models. Whereas the preliminary evidence indicates that the heteromeric P2X_4/7 receptor is sensitive to both P2X₄ and P2X₇ receptor antagonists, further research is needed to clearly differentiate the pharmacological properties of the heteromeric P2X_4/7 receptor from its homomeric partners.

To date, no selective P2X receptor antagonists have been evaluated clinically for the relief of pain. Whereas reduced pain sensation was noted in a suramin phase 1 cancer clinical trial (Ho et al., 1992), the clinical utility of receptor-selective P2 antagonists for pain relief has not yet been established. The emerging data on P2 receptor-selective antagonists provides intriguing promise that potentially useful drug candidates can be found that specifically target individual P2 receptor subtypes. Although the P2 receptor-selective compounds identified to date have proven to be useful pharmacological tools in preclinical studies, further effort is needed to identify compounds with the drug-like properties required to interrogate the potential clinical utility of P2 receptor antagonists for pain.

	Footnotes

 
D.D.-R., S.M., C.-C.S., P.H., and M.F.J. contributed equally to this perspective.

Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

doi:10.1124/jpet.106.105890.

ABBREVIATIONS: ADO, adenosine; ,β-meATP, ,β-methyleneATP; IL-1, interleukin-1; DRG, dorsal root ganglion; TRPV1, transient receptor potential-1; PPADs, pyridoxal phosphate-6-azophenyl-2-4-disulfonic acid; A-317334, S-enantiomer of A-317491.

Address correspondence to: Dr. Michael F. Jarvis, Abbott Laboratories, R4PM, AP9A/311, 100 Abbott Park Road, Abbott Park, IL 60064. E-mail: michael.jarvis{at}abbott.com

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Top Abstract P2X3 and P2X2/3 Receptors P2X4 Receptors P2X7 Receptors P2Y Receptors Perspective References

 

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