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The Journal of Neuroscience, December 12, 2007, 27(50):13739-13749; doi:10.1523/JNEUROSCI.3258-07.2007

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Cellular/Molecular
Tonic Endovanilloid Facilitation of Glutamate Release in Brainstem Descending Antinociceptive Pathways

Katarzyna Starowicz,^1 * Sabatino Maione,^3 * Luigia Cristino,² Enza Palazzo,³ Ida Marabese,³ Francesca Rossi,³ Vito de Novellis,³ and Vincenzo Di Marzo¹

¹The Endocannabinoid Research Group, Institute of Biomolecular Chemistry and ²Institute of Cybernetics "E. Caianiello," Consiglio Nazionale delle Ricerche, 80078 Pozzuoli, Naples, Italy, and ³Department of Experimental Medicine, Section of Pharmacology "L. Donatelli," Second University of Naples, 80138 Naples, Italy

Correspondence should be addressed to either Vincenzo Di Marzo or Sabatino Maione at the above addresses. Email: vdimarzo{at}icmib.na.cnr.it and Email: sabatino.maione{at}unina2.it

Activation of transient receptor potential vanilloid-1 (TRPV1) channels in the periaqueductal gray (PAG) activates OFF antinociceptive neurons of the rostral ventromedial medulla (RVM). We examined in rats the effect of intra-ventrolateral (VL)-PAG injections of TRPV1 agonists and antagonists on the nocifensive response to heat in the plantar test, neurotransmitter (glutamate and GABA) release in the RVM, and spontaneous and tail flick-related activities of RVM neurons. The localization of TRPV1 in VL-PAG and RVM neurons was examined using various markers of glutamatergic and GABAergic neurons. Intra-VL-PAG injection of capsaicin increased the threshold of thermal pain sensitivity, whereas the selective TRPV1 antagonist 5'-iodo-resiniferatoxin (I-RTX) facilitated nociceptive responses, and blocked capsaicin analgesic effect at a dose inactive per se. Intra-VL PAG capsaicin evoked a robust release of glutamate in RVM microdialysates. I-RTX, at a dose inactive per se, blocked the effect of capsaicin, and inhibited glutamate release at a higher dose. Antinociception and hyperalgesia induced by capsaicin and I-RTX, respectively, correlated with enhanced or reduced activity of RVM OFF cells. Immunohistochemical analyses suggested that several TRPV1-immunoreactive (ir) neurons in both the VL-PAG and RVM are glutamatergic and surrounded by glutamatergic and GABAergic terminals. Our data suggest that VL-PAG neurons respond to TRPV1 stimulation by releasing glutamate into the RVM, thereby activating OFF cells and producing analgesia. The results obtained with the TRPV1 antagonist alone suggest that this pathway is tonically activated by endovanilloids.

Key words: TRPV1; pain; glutamate; periaqueductal gray; descending pathway; endovanilloid

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Received July 18, 2007; revised Sept. 24, 2007; accepted Oct. 24, 2007.

Correspondence should be addressed to either Vincenzo Di Marzo or Sabatino Maione at the above addresses. Email: vdimarzo{at}icmib.na.cnr.it and Email: sabatino.maione{at}unina2.it

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