Tonic Endovanilloid Facilitation of Glutamate Release in Brainstem Descending Antinociceptive Pathways

Abstract

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 5Ј-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.

Genotype-dependent responsivity to inflammatory pain: A role for TRPV1 in the periaqueductal grey

“…[3]RTX autoradiography, IHC, ISH, genetic-modified reporter (Casarotto et al, 2012b;Cavanaugh et al, 2011;Cristino et al, 2006;McGaraughty et al, 2003;Mezey et al, 2000;Roberts et al, 2004;Starowicz et al, 2007;Tóth et al, 2005) 38 Cell bodies/axons PAG Immunohistochemistry Rats Cytoplasm, axons of neurons VLPAG Immunohistochemistry Rats (Maione et al, 2006) VGAT and VGLUT neurons VLPAG Immunohistochemistry Rats (Starowicz et al, 2007) Neurons VLPAG Electrophysiological recordings Rats (Liao et al, 2011) Astrocytes and pericytes PAG Immunohistochemistry Rats (Tóth et al, 2005) Neurons DPAG Immunohistochemistry Rats (Casarotto et al, 2012a) …”

“…Capsaicin, when injected into the dorsolateral periaqueductal grey (DLPAG), increased the latency of nociceptive responding to noxious heat, indicating that stimulation of TRPV1 within the descending inhibitory pain pathway can cause antinociception (Palazzo et al, 2002). Microinjection of capsaicin into the ventrolateral periaqueductal grey (VLPAG ) increased the threshold of thermal pain sensitivity in rats (Starowicz et al, 2007). Opposite effects were found with 5'-IRTX, a selective TRPV1 antagonist that facilitated nociceptive responses and, at an inactive dose, abolished capsaicin-mediated antinociception, implying that the effect of capsaicin is mediated by TRPV1 in the VLPAG (Maione et al, 2006).…”

“…The antinociceptive effect of intra-VLPAG capsaicin was accompanied by an increase in glutamate release in the RVM as measured by in vivo microdialysis, which was also blocked by a per se inactive dose of I-RTX. The TRPV1 antagonist itself reduced the release of glutamate, thus suggesting that VLPAG TRPV1 tonically stimulates glutamatergic output to the RVM with a concomitant inhibition of nociception (Starowicz et al, 2007). Hyperalgesia or analgesia have been observed following intra-VLPAG administration of the fatty acid amide hydrolase inhibitor (FAAH) URB597 depending on whether VLPAG cannabinoid receptors or TRPV1 have been activated (Maione et al, 2006).…”

“…The ON and OFF neurons in the RVM have been shown to respond to capsaicin administered into the PAG (Maione et al, 2006;McGaraughty et al, 2003;Starowicz et al, 2007). Intra-DLPAG microinjection of capsaicin is followed by a decrease in the tail flick-related ON cell burst activity and an increase in the tail flick latency (McGaraughty et al, 2003).…”

Role of TRPV1 receptors in descending modulation of pain

“…It can be activated not only by exogenous agents such as capsaicin (the pungent ingredient of hot pepper) or resiniferatoxin (isolated from cactus-like plant) but also by many endogenous stimuli, including heat (>43°), low pH and endovanilloids (Caterina et al, 1997;Chuang et al, 2001;De Petrocellis et al, 2004;Ferreira et al, 2004;Premkumar and Ahern, 2000;Tominaga et al, 1998;Szallasi and Blumberg, 1999;Starowicz et al, 2007a). The role of TRPV1 receptor in pain-related behaviour has been definitely demonstrated using TRPV1 receptor gene knockout mice, which showed impairment in detecting thermal painful stimuli without altered mechanical noxious responses (Caterina et al, 2000).…”