Spinal cord mechanisms mediating behavioral hyperalgesia induced by neurokinin-1 tachykinin receptor activation in the rostral ventromedial medulla.
Hyperalgesia in animal injury models is linked to activation of descending raphespinal modulatory circuits originating in the rostral ventromedial medulla (RVM). A neurokinin-1 (NK-1) receptor antagonist microinjected into the RVM before or after inflammation produced by complete Freund's adjuvant (CFA) resulted in an attenuation of thermal hyperalgesia. A transient (acute) or a continuous infusion of Substance P (SP) microinjected into the RVM of non-inflamed animals led to similar pain hypersensitivity. Intrathecal pretreatment or post-treatment of a 5-HT3 receptor antagonist (Y-25130 or ondansetron) blocked the SP-induced hyperalgesia. The SP-induced hyperalgesia was both GABA(A) and NMDA receptor-dependent after pre- and post-treatment with selective antagonists at the spinal level. A microinjection of SP into the RVM also led to increased NMDA NR1 receptor subunit phosphorylation in spinal cord tissue. The GABA(A) receptor-mediated hyperalgesia involved a shift in the anionic gradient in dorsal horn nociceptive neurons and an increase in phosphorylated NKCC1 protein (isoform of the Na-K-Cl cotransporter). Following a low dose of SP infused into the RVM, intrathecal muscimol (GABA(A) agonist) increased SP-induced thermal hyperalgesia, phosphorylated NKCC1 protein expression, and NMDA NR1 subunit phosphorylation in the spinal cord. The thermal hyperalgesia was blocked by intrathecal gabazine, the GABA(A) receptor antagonist, and MK-801, the NMDA receptor channel blocker. These findings indicate that NK-1 receptors in the RVM are involved in SP-induced thermal hyperalgesia, this hyperalgesia is 5-HT3-receptor dependent at the spinal level, and involves the functional interaction of spinal GABA(A) and NMDA receptors.
Lagraize
S C
SC
University of Maryland Dental School, Department of Neural and Pain, Sciences, Program in Neuroscience, 650 W. Baltimore Street, 8-South, Baltimore, MD 21201, USA. slagraize@umaryland.edu
Guo
W
W
Yang
K
K
Wei
F
F
Ren
K
K
Dubner
R
R
D000818:Animals; D001522:Behavior, Animal; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005620:Freund's Adjuvant; D018682:GABA Agents / Q000494:pharmacology; D006930:Hyperalgesia / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D008845:Microinjections / Q000379:methods; D009118:Muscimol / Q000494:pharmacology; D017294:Ondansetron / Q000494:pharmacology; D010078:Oxazines / Q000494:pharmacology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D020671:Posterior Horn Cells / Q000187:drug effects / Q000502:physiology; D011724:Pyridazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism*; D013373:Substance P / Q000494:pharmacology; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D019086:Bridged Bicyclo Compounds, Heterocyclic; D018691:Excitatory Amino Acid Antagonists; D018682:GABA Agents; D010078:Oxazines; D011724:Pyridazines; D018040:Receptors, Neurokinin-1; D012702:Serotonin Antagonists; C086089:3,5-bis(trifluoromethyl)benzyl N-acetyltryptophan; D009118:Muscimol; D013373:Substance P; D017294:Ondansetron; D016291:Dizocilpine Maleate; C070671:azasetron; D014364:Tryptophan; D005620:Freund's Adjuvant; C049853:gabazine