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1.
J Thromb Haemost ; 15(6): 1223-1235, 2017 06.
Article in English | MEDLINE | ID: mdl-28345287

ABSTRACT

Essentials The role of platelet P2Y12 receptors in the regulation of chronic inflammatory pain is unknown. Complete Freund's Adjuvant (CFA)-induced chronic inflammatory pain model was used in mice. Gene deficiency and antagonists of P2Y12 receptors attenuate hyperalgesia and local inflammation. Platelet P2Y12 receptors contribute to these effects in the chronic phase of inflammation. SUMMARY: Background P2Y12 receptor antagonists are widely used in clinical practice to inhibit platelet aggregation. P2Y12 receptors are also known to regulate different forms of pain as well as local and systemic inflammation. However, it is not known whether platelet P2Y12 receptors contribute to these effects. Objectives To explore the contribution of platelet P2Y12 receptors to chronic inflammatory pain in mice. Methods Complete Freund's adjuvant (CFA)-induced chronic inflammatory pain was induced in wild-type and P2ry12 gene-deficient (P2ry12-/- ) mice, and the potent, direct-acting and reversible P2Y12 receptor antagonists PSB-0739 and cangrelor were used. Results CFA-induced mechanical hyperalgesia was significantly decreased in P2ry12-/- mice for up to 14 days, and increased neutrophil myeloperoxidase activity and tumor necrosis factor (TNF)-α and CXCL1 (KC) levels in the hind paws were also attenuated in the acute inflammation phase. At day 14, increased interleukin (IL)-1ß, IL-6, TNF-α and KC levels were attenuated in P2ry12-/- mice. PSB-0739 and cangrelor reversed hyperalgesia in wild-type mice but had no effect in P2ry12-/- mice, and PSB-0739 was also effective when applied locally. The effects of both local and systemic PSB-0739 were prevented by A-803467, a selective NaV1.8 channel antagonist, suggesting the involvement of NaV1.8 channels in the antihyperalgesic effect. Platelet depletion by anti-mouse CD41 antibody decreased hyperalgesia and attenuated the proinflammatory cytokine response in wild-type but not in P2ry12-/- mice on day 14. Conclusions In conclusion, P2Y12 receptors regulate CFA-induced hyperalgesia and the local inflammatory response, and platelet P2Y12 receptors contribute to these effects in the chronic inflammation phase.


Subject(s)
Blood Platelets/drug effects , Chronic Pain/chemically induced , Freund's Adjuvant/chemistry , Inflammation/chemically induced , Receptors, Purinergic P2Y12/chemistry , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Aniline Compounds/chemistry , Animals , Blood Platelets/metabolism , Chemokine CXCL1/metabolism , Cytokines/metabolism , Furans/chemistry , Hyperalgesia , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Pain , Time Factors , Tumor Necrosis Factor-alpha/metabolism
2.
Neuropharmacology ; 85: 538-47, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24973707

ABSTRACT

We have earlier shown that PACAP-38 decreases neurogenic inflammation. However, there were no data on its receptorial mechanism and the involvement of its PAC1 and VPAC1/2 receptors (PAC1R, VPAC1/2R) in this inhibitory effect. Neurogenic inflammation in the mouse ear was induced by topical application of the Transient Receptor Potential Ankyrin 1 (TRPA1) receptor activator mustard oil (MO). Consequent neurogenic edema, vasodilation and plasma leakage were assessed by measuring ear thickness with engineer's micrometer, detecting tissue perfusion by laser Doppler scanning and Evans blue or indocyanine green extravasation by intravital videomicroscopy or fluorescence imaging, respectively. Myeloperoxidase activity, an indicator of neutrophil infiltration, was measured from the ear homogenates with spectrophotometry. The selective PAC1R agonist maxadilan, the VPAC1/2R agonist vasoactive intestinal polypeptide (VIP) or the vehicle were administered i.p. 15 min before MO. Substance P (SP) concentration of the ear was assessed by radioimmunoassay. Maxadilan significantly diminished MO-induced neurogenic edema, increase of vascular permeability and vasodilation. These inhibitory effects of maxadilan may be partially due to the decreased substance P (SP) levels. In contrast, inhibitory effect of VIP on ear swelling was moderate, without any effect on MO-induced plasma leakage or SP release, however, activation of VPAC1/2R inhibited the increased microcirculation caused by the early arteriolar vasodilation. Neither the PAC1R, nor the VPAC1/2R agonist influenced the MO-evoked increase in tissue myeloperoxidase activity. These results clearly show that PAC1R activation inhibits acute neurogenic arterial vasodilation and plasma protein leakage from the venules, while VPAC1/2R stimulation is only involved in the attenuation of vasodilation.


Subject(s)
Insect Proteins/pharmacology , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/agonists , Skin Physiological Phenomena/drug effects , Vasoconstrictor Agents/pharmacology , Vasodilation/drug effects , Animals , Capillary Permeability/drug effects , Capillary Permeability/physiology , Disease Models, Animal , Ear/pathology , Ear/physiopathology , Edema , Female , Male , Mice , Microcirculation/drug effects , Microcirculation/physiology , Mustard Plant , Peroxidase/metabolism , Plant Oils , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism , Receptors, Vasoactive Intestinal Peptide, Type II/agonists , Receptors, Vasoactive Intestinal Peptide, Type II/metabolism , Receptors, Vasoactive Intestinal Polypeptide, Type I/agonists , Receptors, Vasoactive Intestinal Polypeptide, Type I/metabolism , Substance P/metabolism , Vasoactive Intestinal Peptide/pharmacology , Vasodilation/physiology
3.
Neuropeptides ; 44(5): 363-71, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20621353

ABSTRACT

Pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) and its receptors (PAC1 and VPAC) have been shown in the spinal dorsal horn, dorsal root ganglia and sensory nerve terminals. Data concerning the role of PACAP in central pain transmission are controversial and we have recently published its divergent peripheral effects on nociceptive processes. The aim of the present study was to investigate acute somatic and visceral nocifensive behaviours, partial sciatic nerve ligation-evoked chronic neuropathic, as well as resiniferatoxin-induced inflammatory thermal and mechanical hyperalgesia in PACAP deficient (PACAP(-/-)) mice to elucidate its overall function in pain transmission. Neuronal activation was investigated with c-Fos immunohistochemistry. Paw lickings in the early (0-5 min) and late (20-45 min) phases of the formalin test were markedly reduced in PACAP(-/-) mice. Acetic acid-evoked abdominal contractions referring to acute visceral chemonociception was also significantly attenuated in PACAP knockout animals. In both models, the excitatory role of PACAP was supported by markedly greater c-Fos expression in the periaqueductal grey and the somatosensory cortex. In PACAP-deficient animals neuropathic mechanical hyperalgesia was absent, while c-Fos immunopositivity 20 days after the operation was significantly higher. In this chronic model, these neurons are likely to indicate the activation of secondary inhibitory pathways. Intraplantarly injected resiniferatoxin-evoked mechanical hyperalgesia involving both peripheral and central processes was decreased, but thermal allodynia mediated by only peripheral mechanisms was increased in PACAP(-/-) mice. These data clearly demonstrate an overall excitatory role of PACAP in pain transmission originating from both exteroceptive and interoceptive areas, it is also involved in central sensitization. This can be explained by the signal transduction mechanisms of its identified receptors, both PAC1 and VPAC activation leads to neuronal excitation. In contrast, it is an inhibitory mediator at the level of the peripheral sensory nerve endings and decreases their sensitization to heat with presently unknown mechanisms.


Subject(s)
Behavior, Animal/physiology , Hyperalgesia/metabolism , Neurons/metabolism , Nociceptors/physiology , Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism , Analysis of Variance , Animals , Hot Temperature , Hyperalgesia/genetics , Hyperalgesia/physiopathology , Immunohistochemistry , Mice , Mice, Knockout , Pain Measurement , Periaqueductal Gray/metabolism , Pituitary Adenylate Cyclase-Activating Polypeptide/genetics , Proto-Oncogene Proteins c-fos/metabolism , Somatosensory Cortex/metabolism
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