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This Article Full Text Full Text (PDF) All Versions of this Article: 101/5/2411    most recent 91225.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Maione, S. Articles by Di Marzo, V. Search for Related Content PubMed PubMed Citation Articles by Maione, S. Articles by Di Marzo, V.

Functional Interaction Between TRPV1 and µ-Opioid Receptors in the Descending Antinociceptive Pathway Activates Glutamate Transmission and Induces Analgesia

¹Endocannabinoid Research Group, Second University of Naples, Department of Experimental Medicine, Naples; ²Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy; ³Department of Pain Pharmacology, Institute of Pharmacology Polish Academy of Science, Cracow, Poland; and ⁴Department of Pediatrics, Second University of Naples, Naples, Italy

Submitted 18 November 2008; accepted in final form 10 March 2009

The transient receptor potential vanilloid-1 (TRPV1) receptor is involved in peripheral and spinal nociceptive processing and is a therapeutic target for pain. We have shown previously that TRPV1 in the ventrolateral periaqueductal gray (VL-PAG) tonically contributes to brain stem descending antinociception by stimulating glutamate release into the rostral ventromedial medulla and OFF neuron activity. Because both opioid and vanilloid systems integrate and transduce pain sensation in these pathways, we studied the potential interaction between TRPV1 and µ-opioid receptors in the VL-PAG–rostral ventromedial medulla (RVM) system. We found that the TRPV1 agonist, capsaicin, and the µ-receptor agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]enkephalin, when coadministered into the ventrolateral-PAG at doses nonanalgesic per se, produce 1) antinociception in tests of thermal nociception; 2) stimulation of glutamate release into the RVM; and 3) inhibition of ON neuron activity in the RVM. These effects were all antagonized by the TRPV1 and opioid receptor antagonists 5'-iodo-resiniferatoxin and naloxone, respectively, thus suggesting the existence of a TRPV1–µ-opioid interaction in the VL-PAG–RVM system. By using double immunofluorescence techniques, we found that TRPV1 and µ-opioid receptors are coexpressed in several neurons of the VL-PAG. These findings suggest that µ-receptor activation not only acts on inhibitory neurons to disinhibit PAG output neurons but also interacts with TRPV1 activation at increasing glutamate release into the RVM, possibly by acting directly on PAG output neurons projecting to the RVM.