ABSTRACT
The intrathecal (i.t.) injection of substance P (SP) and N-methyl-D-aspartate (NMDA) induce transient nociceptive response by activating neurokinin (NK) 1 and NMDA receptors, respectively. We have recently reported that angiotensin (Ang) (1-7), an N-terminal fragment of Ang II, could alleviate several types of pain including neuropathic and inflammatory pain by activating spinal MAS1. Here, we investigated whether Ang (1-7) can inhibit the SP- and NMDA-induced nociceptive response. The nociceptive response induced by an i.t. injection of SP or NMDA was assessed by measuring the duration of hindlimb scratching directed toward the flank, biting and/or licking of the hindpaw or the tail for 5 min. Localization of MAS1 and either NK1 or NMDA receptors in the lumbar superficial dorsal horn was determined by immunohistochemical observation. The nociceptive response induced by SP and NMDA was attenuated by the i.t. co-administration of Ang (1-7) (0.03-3 pmol) in a dose-dependent manner. The inhibitory effects of Ang (1-7) (3 pmol) were attenuated by A779 (100 pmol), a MAS1 antagonist. Moreover, immunohistochemical analysis showed that spinal MAS1 co-localized with NK1 receptors and NMDA receptors on cells in the dorsal horn. Taken together, the i.t. injection of Ang (1-7) attenuated the nociceptive response induced by SP and NMDA via spinal MAS1, which co-localized with NK1 and NMDA receptors. Thus, the spinal Ang (1-7)/MAS1 pathway could represent a therapeutic target to effectively attenuate spinal pain transmission caused by the activation of NK1 or NMDA receptors.
Subject(s)
Angiotensin I/administration & dosage , Nociception/drug effects , Nociceptive Pain/drug therapy , Peptide Fragments/administration & dosage , Proto-Oncogene Proteins/agonists , Receptors, G-Protein-Coupled/agonists , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Humans , Injections, Spinal , Male , Mice , N-Methylaspartate/administration & dosage , N-Methylaspartate/adverse effects , Nociceptive Pain/chemically induced , Nociceptive Pain/diagnosis , Proto-Oncogene Mas , Proto-Oncogene Proteins/metabolism , Receptors, G-Protein-Coupled/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Receptors, Neurokinin-1/metabolism , Spinal Cord/drug effects , Spinal Cord/metabolism , Substance P/administration & dosage , Substance P/adverse effectsABSTRACT
We have previously demonstrated that the phosphorylation of p38 MAPK, through spinal AT1 receptor activation, is involved in formalin-induced nociception and follows accompanied by the increase in spinal angiotensin (Ang) II levels. We have also found that Ang (1-7), an N-terminal fragment of Ang II generated by ACE2, prevents the Ang II-induced nociceptive behavior via spinal MAS1 and the inhibition of p38 MAPK phosphorylation. Here, we examined whether the ACE2 activator diminazene aceturate (DIZE) can prevent the formalin-induced nociception in mice. The i.t. administration of DIZE attenuated the second, but not the first phase of formalin-induced nociceptive response. An increase in the activity of spinal ACE2 was measured following DIZE administration. The inhibitory effect of DIZE on nociception was abolished by the i.t. co-administration of the MAS1 antagonist A779. The i.t. administration of Ang (1-7) showed a similar effect on the second phase of the response which was also attenuated by A779. Furthermore, DIZE and Ang (1-7) each inhibited the formalin-induced phosphorylation of p38 MAPK on the dorsal lumbar spinal cord. This inhibition was again prevented by A779. ACE2 was expressed in neurons and microglia but absent from astrocytes in the superficial dorsal horn. Our data show that the i.t.-administered DIZE attenuates the second phase of the formalin-induced nociception which is accompanied by the inhibition of p38 MAPK phosphorylation. They also suggest the involvement of MAS1 activation on spinal neurons and microglia in response to the increase in Ang (1-7) following ACE2 activation.
Subject(s)
Diminazene/analogs & derivatives , Pain/drug therapy , Peptidyl-Dipeptidase A/metabolism , Spinal Cord/drug effects , p38 Mitogen-Activated Protein Kinases/metabolism , Angiotensin I/pharmacology , Angiotensin II/analogs & derivatives , Angiotensin II/pharmacology , Angiotensin-Converting Enzyme 2 , Animals , Diminazene/administration & dosage , Disease Models, Animal , Formaldehyde/toxicity , Humans , Injections, Spinal , Male , Mice , Microglia/metabolism , Neurons/metabolism , Nociception/drug effects , Nociception/physiology , Pain/chemically induced , Peptide Fragments/pharmacology , Phosphorylation/drug effects , Proto-Oncogene Mas , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/metabolism , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, G-Protein-Coupled/metabolism , Spinal Cord/cytology , Spinal Cord/metabolismABSTRACT
The intriguing difference between far-infrared photoconductivity spectroscopy and absorption spectroscopy in the measurement of the magnetoplasmon frequency in GaAs quantum wells reported by Holland et al. [Phys. Rev. Lett. 93, 186804 (2004)] remains unexplained to date. This Letter provides a consistent mechanism to solve this puzzle. The mechanism is based on the electron reservoir model for the integer quantum Hall effect in graphene [Phys. Lett. A 376, 616 (2012)]. We predict sharp kinks to appear in the magnetic induction dependence of the magnetoplasmon frequency at very low temperatures such as 14 mK in the same GaAs quantum well sample used by Holland et al.
