Spinal cord mechanisms mediating behavioral hyperalgesia induced by neurokinin-1 tachykinin receptor activation in the rostral ventromedial medulla

Neuroscience. 2010 Dec 29;171(4):1341-56. doi: 10.1016/j.neuroscience.2010.09.040. Epub 2010 Oct 1.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Behavior, Animal
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Disease Models, Animal
  • Dizocilpine Maleate / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Interactions
  • Excitatory Amino Acid Antagonists / pharmacology
  • Freund's Adjuvant
  • GABA Agents / pharmacology
  • Hyperalgesia / etiology
  • Hyperalgesia / pathology*
  • Hyperalgesia / prevention & control
  • In Vitro Techniques
  • Inflammation / chemically induced
  • Inflammation / complications
  • Male
  • Medulla Oblongata / drug effects
  • Medulla Oblongata / metabolism*
  • Membrane Potentials / drug effects
  • Microinjections / methods
  • Muscimol / pharmacology
  • Ondansetron / pharmacology
  • Oxazines / pharmacology
  • Pain Measurement
  • Pain Threshold / drug effects
  • Pain Threshold / physiology*
  • Posterior Horn Cells / drug effects
  • Posterior Horn Cells / physiology
  • Pyridazines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Reaction Time / drug effects
  • Reaction Time / physiology
  • Receptors, Neurokinin-1 / metabolism*
  • Serotonin Antagonists / pharmacology
  • Spinal Cord / cytology
  • Spinal Cord / metabolism*
  • Substance P / pharmacology
  • Tryptophan / analogs & derivatives
  • Tryptophan / pharmacology
  • Up-Regulation / drug effects


  • Bridged Bicyclo Compounds, Heterocyclic
  • Excitatory Amino Acid Antagonists
  • GABA Agents
  • Oxazines
  • Pyridazines
  • Receptors, Neurokinin-1
  • Serotonin Antagonists
  • 3,5-bis(trifluoromethyl)benzyl N-acetyltryptophan
  • Muscimol
  • Substance P
  • Ondansetron
  • Dizocilpine Maleate
  • azasetron
  • Tryptophan
  • Freund's Adjuvant
  • gabazine