Peripheral mechanisms underlying the essential role of P2X7 receptors in the development of inflammatory hyperalgesia.

Activation of P2X7 receptors by endogenous ATP contributes to the development of inflammatory hyperalgesia. Given the clinical importance of mechanical hyperalgesia in inflammatory states, we hypothesized that the activation of the P2X7 receptor by endogenous ATP contributes to carrageenan-induced mechanical hyperalgesia, and that this contribution is mediated by an indirect sensitization of the primary afferent nociceptors. Co-administration of the selective P2X7 receptor antagonist, A-438079, or the P2X7 receptor antagonist, oATP, with carrageenan blocked the mechanical hyperalgesia induced by carrageenan and significantly reduced the increased concentration of TNF-alpha, IL-6 and CINC-1, but not of IL-1beta induced by carrageenan in the subcutaneous tissue of the rat's hind paw. We concluded that the activation of P2X7 receptors by endogenous ATP is essential to the development of the mechanical hyperalgesia induced by carrageenan in the subcutaneous tissue. It is suggested that this essential role of P2X7 receptors in the development of carrageenan-induced mechanical hyperalgesia is mediated by an indirect sensitization of the primary afferent nociceptors dependent on the previous release of TNF-alpha, IL-6 and CINC-1, but not of IL-1beta.

Involvement of temporomandibular joint P2X3 and P2X2/3 receptors in carrageenan-induced inflammatory hyperalgesia in rats.

The aim of this study was to investigate the role of P2X3, P2X2/3 and P2X7 receptors in the development of TMJ hyperalgesia induced by carrageenan. We also investigated the expression of mRNA of P2X7 receptors in the trigeminal ganglia and the existence of functional P2X7 receptors in the rat's TMJ. The P2X1, P2X3 and P2X2/3 receptor antagonist TNP-ATP, but not the selective P2X7 receptor antagonist A-438079, significantly reduced carrageenan-induced TMJ inflammatory hyperalgesia. The qPCR assay showed that mRNA of P2X7 receptors are expressed in the trigeminal ganglia but this expression is not increased by the inflammation induced by carrageenan in the TMJ region. The P2X7 receptor agonist BzATP induced TMJ inflammatory hyperalgesia that was significantly reduced by pretreatment with dexamethasone. These results indicate that P2X3 and P2X2/3 but not P2X7 receptors are involved in carrageenan-induced TMJ inflammatory hyperalgesia. However, functional P2X7 receptors are expressed in the TMJ region. The activation of these receptors by BzATP sensitizes the primary afferent nociceptors in the TMJ through the previous release of inflammatory mediators. The findings of this study point out P2X3 and P2X2/3 receptors, but not P2X7 receptors, as potential targets for the development of new analgesic drugs to control TMJ inflammatory pain.

Peripheral mechanisms underlying the essential role of P2X3,2/3 receptors in the development of inflammatory hyperalgesia.

Activation of P2X3,2/3 receptors by endogenous ATP contributes to the development of inflammatory hyperalgesia. Given the clinical importance of mechanical hyperalgesia in inflammatory states, we hypothesized that the activation of P2X3,2/3 receptors by endogenous ATP contributes to carrageenan-induced mechanical hyperalgesia and that this contribution is mediated by an indirect and/or a direct sensitization of the primary afferent nociceptors. Co-administration of the selective P2X3,2/3 receptors antagonist A-317491, or the non-selective P2X3 receptor antagonist, TNP-ATP, with carrageenan blocked the mechanical hyperalgesia induced by carrageenan, and significantly reduced the increased concentration of tumor necrosis factor alpha (TNF-alpha) and chemokine-induced chemoattractant-1 (CINC-1) but not of interleukin-1 beta (IL-1 beta) induced by carrageenan. Co-administration of the selective P2X3,2/3 receptors antagonist A-317491 with carrageenan did not affect the neutrophil migration induced by carrageenan. Intrathecal administration of oligonucleotides antisense against P2X3 receptors for seven days significantly reduced the expression of P2X3 receptors in the saphenous nerve and significantly reduced the mechanical hyperalgesia induced by carrageenan. We concluded that the activation of P2X3,2/3 receptors by endogenous ATP is essential to the development of the mechanical hyperalgesia induced by carrageenan. Furthermore, we showed that this essential role of P2X3,2/3 receptors in the development of carrageenan-induced mechanical hyperalgesia is mediated by an indirect sensitization of the primary afferent nociceptors dependent on the previous release of TNF-alpha and by a direct sensitization of the primary afferent nociceptors.

Nerve growth factor acts with the beta2-adrenoceptor to induce spontaneous nociceptive behavior during temporomandibular joint inflammatory hyperalgesia.

AIMS: The aim of this study was to investigate whether the injection of nerve growth factor induces spontaneous nociceptive behavior in the intact or sensitized temporomandibular joint (TMJ) of rats. MAIN METHODS: NGF was injected into the TMJ 1 h after the TMJ injection of saline or carrageenan and the spontaneous nociceptive behavior was quantified. The mechanism involved in this phenomenon was investigated by the injection of NGF into the carrageenan-sensitized TMJ in the presence of indomethacin or of beta-adrenergic antagonists. KEY FINDINGS: NGF injected into the TMJ sensitized by a prior TMJ injection of carrageenan but not into the intact TMJ induced a significant nociceptive behavior. Co-injection of the non-specific Trk receptor antagonist k252A with NGF 1 h after the TMJ injection of carrageenan significantly reduced NGF-induced spontaneous nociception supporting the Trk receptor activation in this nociceptive effect. Blockade of prostaglandin synthesis by indomethacin before the TMJ injection of carrageenan did not reduce NGF-induced nociception. Co-administration of carrageenan with the beta2-adrenoceptor antagonist ICI 118.55 but not with the beta1-adrenoceptor antagonist atenolol significantly reduced NGF-induced nociception. The injection of NGF the TMJ sensitized by a previous TMJ injection of epinephrine also induced nociceptive behavior. SIGNIFICANCE: Taken together, these results indicate that NGF can induce TMJ nociception during TMJ inflammation. Moreover, the expression of this nociceptive response seems to depend on the synergic activity of NGF and sympathetic amines released during TMJ inflammation acting on beta2-adrenergic receptors.

Smoking modulates interferon-gamma expression in the gingival tissue of patients with chronic periodontitis.

Although interferon-gamma (IFN-gamma) plays a critical role in periodontitis, no information is available regarding the effect of smoking on this cytokine in the periodontium. Therefore, this study aimed to evaluate the effect of smoking on the IFN-gamma levels in gingival tissue from patients with chronic periodontitis. Sixty-two patients were assigned to three groups: healthy [non-smoking and periodontally healthy individuals (probing depth or= 5 mm and bleeding on probing; n = 25)]; and smoking [smokers (>or= 1 pack/day for at least 10 yr) diagnosed with chronic periodontitis (n = 25)]. Gingival biopsies were analyzed by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Regardless of smoking status, diseased patients presented higher levels of IFN-gamma than peridontally healthy patients. In sites with comparable types of periodontitis, smoking increased both protein and mRNA levels of IFN-gamma in gingival tissue. Within the limits of this study, it can be concluded that modulation of periodontal tissue destruction by smoking may involve its effect on IFN-gamma production.

Evidence for the involvement of endogenous ATP and P2X receptors in TMJ pain.

Evidence is accumulating which supports a role for ATP in the initiation of pain by acting on P2X receptors expressed on nociceptive afferent nerve terminals. To investigate whether these receptors play a role in temporomandibular (TMJ) pain, we studied the presence of functional P2X receptors in rat TMJ by examining the nociceptive behavioral response to the application of the selective P2X receptor agonist alpha,beta-methylene ATP (alpha,beta-meATP) into the TMJ region of rat. The involvement of endogenous ATP in the development of TMJ inflammatory hyperalgesia was also determined by evaluating the effect of the general P2 receptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) on carrageenan-induced TMJ inflammatory hyperalgesia. Application of alpha,beta-meATP into the TMJ region of rats produced significant nociceptive responses that were significantly reduced by the co-application of lidocaine N-ethyl bromide quaternary salt, QX-314, (2%) or of the P2 receptor antagonist PPADS. Co-application of PPADS with carrageenan into the TMJ significantly reduced inflammatory hyperalgesia. The results indicate that functional P2X receptors are present in the TMJ and suggest that endogenous ATP may play a role in TMJ inflammatory pain mechanisms possibly by acting primarily in these receptors.