Axonal transport of VR1 capsaicin receptor mRNA in primary afferents and its participation in inflammation‐induced increase in capsaicin sensitivity

Abstract

Capsaicin receptors are expressed in primary sensory neurons and excited by heat and protons. We examined the in¯ammation-induced changes of the level of VR1 capsaicin receptor mRNA in sensory neurons and the sensitivity of primary afferents to capsaicin. Carrageenan treatment induced axonal transport of VR1 mRNA, but not that of preprotachykinin mRNA, from the dorsal root ganglia to central and peripheral axon terminals. The sensitivity of central terminals to capsaicin, which was estimated by measuring the capsaicin-evoked release of glutamate from the dorsal horn, was increased by peripheral in¯ammation, and such an increase was suppressed by inhibiting the RNA translation in the dorsal horn with cycloheximide and an intrathecal injection of VR1 antisense oligonucleotides. Thus, peripheral in¯ammation induces the axonal transport of VR1 mRNA, which may be involved in the hypersensitivity of primary afferents to capsaicin and the production of in¯ammatory hyperalgesia. Keywords: axonal transport, capsaicin sensitivity, carrageenan in¯ammation, glutamate release, primary afferent, VR1 capsaicin receptor mRNA.Subcutaneous injection of carrageenan into the hind paw induces in¯ammation, a decrease in nociceptive threshold (Kayser et al. 1991) and hyperexcitability of primary afferents (Coggeshall et al. 1983). Nociceptive primary afferents are sensitive to capsaicin. Capsaicin induces the excitation of nociceptors (Such and Jancso 1986; Holzer 1991) and the release of pain transmitters such as glutamate (Ueda et al. 1993; and neuropeptides (Yaksh et al. 1980;Saria et al. 1986). Capsaicin receptor is called a`proton sensor' and`hot sensor' because of its sensitivity to protons and heat stimulation, respectively (Caterina et al. 1997). When in¯ammation occurs in the periphery, the concentration of protons is increased in injured tissues. Therefore, the activation of capsaicin receptors on the peripheral terminals of primary afferents may be partly involved in in¯ammatory hyperalgesia (Caterina et al. 2000). With regard to the spinal cord, glutamate (Okano et al. 1998) and neuropeptides (Satoh et al. 1992;Okano et al. 1998) are also involved in in¯ammatory hyperalgesia. Peripheral in¯ammation increases capsaicin-evoked release of glutamate and neuropeptides ) from the dorsal horn. Although an increase in the biosynthesis of neurotransmitters in primary sensory neurons may be partly responsible for an increase in capsaicin-evoked release of the neurotransmitters Ohno et al. 1990), it is unclear whether peripheral in¯ammation alters, especially increases, the sensitivity of primary afferent

Activation of TRPV1 Contributes to Morphine Tolerance: Involvement of the Mitogen-Activated Protein Kinase Signaling Pathway

“…These findings imply a potential role of TRPV1 in morphine tolerance and associated thermal hyperalgesia. Previous RT-PCR studies did not show an increase in TRPV1 mRNA levels in the DRG after carrageenan-or complete Freund's adjuvant-induced inflammation (Tohda et al, 2001;Ji et al, 2002, Endres-Becker et al, 2007. We also did not detect the increase in TRPV1 mRNA levels in the DRG of morphinetolerant animals.…”

Role of Mitogen-Activated Protein Kinase Activation in Injured and Intact Primary Afferent Neurons for Mechanical and Heat Hypersensitivity after Spinal Nerve Ligation

“…Our data are very consistent with previous electrophysiological and gene knock-out studies of TRPV1 function (i.e., TRPV1 is required for peripheral sensitization to noxious thermal but not mechanical stimuli) (Caterina et al, 2000;Davis et al, 2000). The present study showed the upregulation in TRPV1 mRNA/protein in the uninjured DRG, although several studies have demonstrated an increase in the TRPV1 protein but not in its mRNA, after peripheral inflammation (Tohda et al, 2001;Ji et al, 2002). The reasons for this discrepancy are not clear, but other reports have shown that inflammation and/or NGF increased TRPV1 mRNA in adult DRG neurons (Winston et al, 2001;Amaya et al, 2003).…”

Mechanisms of Prolonged Presynaptic Ca2+Signaling and Glutamate Release Induced by TRPV1 Activation in Rat Sensory Neurons

“…Although the question of which signals activate TRPV1 in vivo remains a matter of debate, numerous studies imply the importance of spinal cord TRPV1 for pain processing. Indeed, the receptor is significantly upregulated in the dorsal horn during chronic inflammation (Tohda et al, 2001;Luo et al, 2004), and intrathecal administration of either selective TRPV1 antagonists or small interfering RNAs that target TRPV1 produced strong analgesic effects in animal models of inflammatory, neuropathic, and visceral pain (Kelly and Chapman, 2002;Kanai et al, 2005;Christoph et al, 2006). Moreover, significant CNS penetration of orally administered TRPV1 antagonists was required to attenuate pain mediated by central sensitization (Cui et al, 2006).…”

“…At the peripheral terminals of primary nociceptors, TRPV1-mediated Ca 2ϩ influx triggers the release of neuropeptides, which contributes to the development of neurogenic inflammation (Caterina and Julius, 2001). TRPV1 is also found in the central processes of primary afferent neurons (Guo et al, 1999;Hwang et al, 2004), and its expression in the dorsal horn of the spinal cord is upregulated during chronic inflammation (Tohda et al, 2001;Luo et al, 2004). Notably, intrathecal administration of selective TRPV1 antagonists significantly reduces pain associated with inflammation and nerve injury (Kanai et al, 2005;Christoph et al, 2006;Cui et al, 2006).…”