Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The recent discovery of a P2X purinoceptor (a ligand-gated ion channel triggered by ATP) that is selectively expressed by small-diameter sensory neurons has led to the exploration of the sources of ATP involved in the initiation of different types of nociception and pain, including sympathetic nerves, endothelial cells and tumour cells. In addition, the anti-nociceptive actions of adenosine via prejunctional P1(A1) purinoceptors in the spinal cord and the pain-enhancing actions of adenosine via P1(A2) purinoceptors in the periphery have generated great interest in the development of P1 agonists and antagonists, as well as P2X antagonists as potential analgesic drugs.
 ...
PMID:Purinergic receptors: their role in nociception and primary afferent neurotransmission. 879 2

The pronociceptive effects of adenosine 5'-triphosphate (ATP) were examined in the low concentration formalin model (0.5%) by coadministration of ATP, ATP analogs (alpha,beta-methylene-ATP and 2-methylthio-ATP) and antagonists (suramin, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid) with formalin and determining effects on the expression of flinching behaviours. Coadministration of ATP (5-500 nmol) with formalin enhanced phase 2 (12-60 min after injection) but not phase 1 (0-10 min after injection) responses. alpha,beta-methylene-ATP (0.5-50 nmol) but not 2-methylthio-ATP (50-500 nmol) produced a similar enhancement of activity, generating an order of potency of alpha,beta-methylene-ATP, ATP >> 2-methylthio-ATP. This enhancement was primarily expressed in the latter part of phase 2, 30-60 min after injection. Coadministration of suramin 50-500 nmol, a non-selective P2X and P2Y purinoceptor antagonist and pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid 5-500 nmol, a selective P2X purinoceptor antagonist, dose-dependently inhibited the augmentation of the formalin response by ATP 50 nmol, but did not reduce the response to formalin itself. Pretreatment for 30 min with higher doses of suramin inhibited the response to formalin (0.5%, 1.5%) and this appeared to be by a systemically mediated action as it was seen following administration into the contralateral paw. The results of this study provide evidence in support of a P2X purinoceptor mediated augmentation of the pain signal by ATP. The delayed time-course of the effect suggests that it may occur in concert with other mediators that are recruited by the inflammatory process, rather than reflecting a direct depolarization of sensory nerves. Other behavioural paradigms may be required to examine the fast onset, direct effect. Suramin appears to exert both local and systemic effects on the expression of pain behaviours in response to formalin.
 ...
PMID:Peripheral adenosine 5'-triphosphate enhances nociception in the formalin test via activation of a purinergic p2X receptor. 925 43

A novel in vitro intra-arterially perfused adult rat tongue-nerve preparation was used to explore the possible actions of P2X purinoceptor agonists (ATP and alpha,beta-methylene ATP (alpha, beta-meATP)) on sensory nerve terminals innervating the rat tongue. We made whole-nerve recordings of the trigeminal branch of the lingual nerve (LN), which conducts general sensory information (pain, temperature, touch, etc.), and the chorda tympani (CT), which conducts taste information. Changes in LN and CT activity following intra-arterial application of P2X agonists were compared. In seven preparations, bolus close-arterial injection of ATP (30-3000 microM, 0.1 ml) or alpha,beta-meATP (10-300 microM, 0.1 ml) induced a rapid (< 1 s after injection), dose-related increase in LN activity that decayed within a few seconds. The minimal concentration of ATP (100 microM) required to elicit a response was about 10-fold higher than that of alpha,beta-meATP (10 microM). Bolus injection of ATP or alpha,beta-meATP induced a moderate decrease in firing frequency in three of seven CT preparations. LN responses to P2X agonists showed signs of rapid desensitisation with the peak frequency of discharge being smaller when the agonists were applied at short intervals. Suramin (200 microM) or PPADS (200 microM) applied by intra-arterial perfusion each antagonised the rapid increase in LN activity following application of alpha,beta-meATP (100 microM). Capsaicin (10 microM, 0.1 ml, n = 5 preparations) was injected intra-arterially to desensitise nociceptive fibres. This was found to block (n = 2) or greatly reduce (n = 3) the excitatory effects of alpha,beta-meATP (100 microM, 0.1 ml) on LN activity, implying that only capsaicin-sensitive nociceptive fibres in LN were responsive to P2X agonists. In contrast to the consistent excitatory responses in LN activity following fast application of P2X agonists as bolus, a variable and moderate change in discharge rate of LN and no change in CT activity (n = 5) was observed after applying ATP (100-300 microM, n = 21) or alpha,beta-meATP (100-300 microM, n = 14) by intra-arterial perfusion. The variable responses in LN activity to slow perfusion in contrast to close-arterial bolus injection are consistent with activation of the rapidly desensitising P2X3 receptors. In summary, ATP and alpha,beta-meATP preferentially activate general sensory afferent fibres (LN) but not taste fibres (CT). We suggest that the increase in whole-nerve activity of LN following application of P2X agonists represents activation of nociceptive fibres which possess P2X3 receptors. Our data indicate that ATP and P2X3 receptors may play a role in nociception, rather than taste sensation in the tongue.
 ...
PMID:P2X purinoceptor-mediated excitation of trigeminal lingual nerve terminals in an in vitro intra-arterially perfused rat tongue preparation. 1079 Jan 66

P2X3 purinergic receptors are predominantly expressed in dorsal root ganglion (DRG) neurons and play an important role in pain sensation. P2X3-specific antagonists are currently being sought to ameliorate pain in several indications. Understanding how antagonists interact with the P2X3 receptor can aid in the discovery and development of P2X3-specific antagonists. We studied the activity of the noncompetitive antagonist P1, P5-di[inosine-5'] pentaphosphate (IP5I) at the P2X3 receptor, compared with the well studied competitive antagonist TNP-ATP, using a whole-cell voltage-clamp technique in dissociated rat DRG neurons. IP5I blocked alphabeta-methylene ATP (alphabeta-meATP)-evoked P2X3 responses in a concentration-dependent manner (IC50 = 0.6 +/- 0.1 microM). IP5I effectively inhibited P2X3 currents when pre-exposed to desensitized but not unbound receptors. Furthermore, IP5I equally blocked 1 and 10 microM alphabeta-meATP-evoked currents and had no effect on the desensitization rate constant of these currents. This supports the action of IP5I as a noncompetitive antagonist that interacts with the desensitized state of the P2X3 receptor. In contrast, TNP-ATP inhibited the current evoked by 1 microM alphabeta-meATP significantly more than the one evoked by 10 microM alphabeta-meATP. It also significantly slowed down the desensitization rate constant of the current. These results suggest that TNP-ATP acts as a competitive antagonist and competes with alphabeta-meATP at the P2X3 agonist binding site. These findings may help to explain why IP5I acts selectively at the fast-desensitizing P2X1 and P2X3 subtypes of the P2X purinoceptor, while having much less potency at slow-desensitizing P2X2 and P2X(2/3) subtypes that lack the fast desensitized conformational state.
 ...
PMID:The P2X3 antagonist P1, P5-di[inosine-5'] pentaphosphate binds to the desensitized state of the receptor in rat dorsal root ganglion neurons. 1601 55

Butyl benzyl phthalate (BBP) is a plasticizer and causes public concern because of its genomic estrogenic effects via estrogen receptors. We previously found that BBP has non-genomic effects, exerting inhibitory effects on the functional activities of nicotinic acetylcholine receptors (nAChR) in bovine adrenal chromaffin cells. nAChR belongs to the superfamily of neurotransmitter-gated channels, so does P2X purinoceptor that is widely distributed in the nervous system and play a role in pain reactions. In this study, we investigated the effects of BBP on the change of [Ca2+]c (cytosolic calcium ion concentration) under the stimulation of purinoceptors in PC12 cells and found that BBP inhibited ATP-induced [Ca2+]c rise (IC50=8.3 microM). The inhibitory rate of BBP remained under the increase of ATP concentration; therefore, the possibility of competitive inhibition was excluded. The inhibition of BBP on P2Y was excluded because its inhibition on ATP-induced [Ca2+]c rise was not found in the absence of extracellular Ca2+. BBP might have some actions on voltage-operated Ca2+ channels (VOCCs) since BBP inhibited the Ca2+ signaling responding to high K+ stimulation (IC50=1.2 microM). We suggest that BBP inhibits the ATP-induced [Ca2+]c rise via its non-competitive inhibition on P2X purinoceptors and VOCCs in the plasma membrane.
 ...
PMID:Butyl benzyl phthalate blocks Ca2+ signaling coupled with purinoceptor in rat PC12 cells. 1636 Jul 12

Adenosine 5'-triphosphate (ATP) plays an important role in nociceptive processing. We used a mouse model of skin cancer pain to investigate the role of ATP in cancer pain. Orthotopic inoculation of B16-BL6 melanoma cells into the hind paw produced spontaneous licking of the tumor-bearing paw. Intraperitoneal injection of the P2 purinoceptor antagonist suramin suppressed spontaneous licking dose-dependently. Two P2X purinoceptor antagonists also suppressed spontaneous licking. An intraplantar injection of ATP, which did not induce licking in the healthy paw, increased licking of the tumor-bearing paw. Spontaneous firing of the tibial nerve was significantly increased in tumor-bearing mice and was inhibited by suramin. Extracellular concentration of ATP was significantly increased in the tumor-bearing paw than in the normal paw. ATP is concentrated in the culture medium of melanoma, lung cancer and breast cancer cells, but not fibroblasts. The P2X(3) receptor was expressed in about 40% of peripherin-positive small and medium-sized neurons in the dorsal root ganglia. P2X(3)-positive neurons were significantly increased in melanoma-bearing mice. These results suggest that ATP and P2X, especially P2X(3), receptors are involved in skin cancer pain, due to the increased release of ATP and increased expression of P2X(3) receptors in the sensory neurons.
 ...
PMID:Involvement of peripheral adenosine 5'-triphosphate and P2X purinoceptor in pain-related behavior produced by orthotopic melanoma inoculation in mice. 2052 75