TRPV1 Receptor in Expression of Opioid-Induced Hyperalgesia

Abstract

Opiates are currently the mainstay for treatment of moderate to severe pain. However, prolonged administration of opiates has been reported to elicit hyperalgesia in animals and examples of opiate-induced hyperalgesia have been reported in humans as well. In spite of the potential clinical significance of such opiate-induced actions, the mechanisms of opiate-induced hypersensitivity remain unknown. The TRPV1 receptor, a molecular sensor of noxious heat, acts as an integrator of multiple forms of noxious stimuli and plays an important role in the development of inflammation-induced hyperalgesia. As animals treated with opiates show thermal hyperalgesia, we examined the possible role of TRPV1 receptors in the development of morphine-induced hyperalgesia using TRPV1 wild-type (WT) and knock-out (KO) mice and with administration of a TRPV1 antagonist in mice and rats. Administration of morphine by subcutaneous implantation of morphine pellets elicited both thermal and tactile hypersensitivity in TRPV1 WT mice, but not in TRPV1 KO mice. Moreover, oral administration of a TRPV1 antagonist reversed both thermal and tactile hypersensitivity induced by sustained morphine administration in mice and rats. Immunohistochemical analyses indicate that sustained morphine administration modestly increases TRPV1 labeling in the dorsal root ganglia (DRG). In addition, sustained morphine increased flinching and plasma extravasation after peripheral stimulation with capsaicin, suggesting an increase in TRPV1 receptor function in the periphery in morphine treated animals. Collectively our data indicate that the TRPV1 receptor is an essential peripheral mechanism in expression of morphine-induced hyperalgesia. PERSPECTIVE Opioid-induced hyperalgesia possibly limits the usefulness of opioids, emphasizing the value of alternative methods of pain control. We demonstrate that TRPV1 channels play an important role in peripheral mechanisms of opioid-induced hyperalgesia. Such information may lead to the discovery of analgesics lacking such adaptations and improving treatment of chronic pain.

Opioid-induced hypernociception is associated with hyperexcitability and altered tetrodotoxin-resistant Na+ channel function of dorsal root ganglia

“…In addition to tolerance development to the analgesic effects of opiates being a major impediment to pain therapy, chronic opiate-induced hypernociception has become a critical problem. This phenomenon of opiate-induced hypernociception is also demonstrated in several experimental animal models such as thermal and tactile nociception in mice (56) as well as in a rat model of narcotic bowel syndrome (1). Rats develop visceral hyperalgesia to colorectal distension after day 6 of morphine administration (1).…”

“…Therefore, the chronic morphine-induced enhanced TRPV1 function can bring the voltage threshold required for activation of TTX-R Na ϩ channels, which is already shifted to a more hyperpolarized potential by chronic morphine, increasing the probability of hyperexcitability in sensory neurons. The role of TRPV1 channels in chronic opioid-induced hypernociception is supported by studies in TRPV1 knockout mice, where the analgesic effects of acute morphine were not affected by gene deletion of TRPV1 but eliminated the hyperalgesia induced by chronic morphine (56). Whether the chronic morphine-induced changes in TTX-R Na ϩ channels and TRPV1 channels occur in the DRG neurons that express opioid receptors is not known.…”

“…Rats develop visceral hyperalgesia to colorectal distension after day 6 of morphine administration (1). In mice, chronic morphine administration produced thermal as well as tactile hypersensitivity 7 days after morphine pellet implantation (56). The mechanisms involved in the development of opiate-induced hypernociception are not clearly known, but it appears to be a multifactorial neurobiological process, including 1) primary afferent sensitization, 2) altered production, release, and reuptake of excitatory neurotransmitters, 3) second-order neuron sensitization to excitatory neurotransmitters, and 4) increased descending facilitation due to rostral ventromedial medullary neuroplastic changes leading to enhanced primary afferent neurotransmitter release and pain (6,23).…”

Inhibition of CaMKII in the Central Nucleus of Amygdala Attenuates Fentanyl-Induced Hyperalgesia in Rats

“…Although presynaptic CaMKIIa appears to have complex functions in synaptic transmission, studies suggest that presynaptic CaMKIIa enhances vesicle motility and facilitates spontaneous neurotransmitter release through promoting synaptic vesicle translocation and increasing Ca 21 entry (Wang, 2008). The transient receptor potential vanilloid type 1 (TRPV1) channel, which has been reported to be an essential peripheral mechanism in the expression of morphine-induced hyperalgesia (Vardanyan et al, 2009), is involved in the regulation of synaptic transmission centrally (Shoudai et al, 2010) or peripherally (Sikand and Premkumar, 2007) by enhancing glutamate release from nerve endings (Kaeser and Regehr, 2014;Ramírez-Barrantes et al, 2016). In view of the fact that both TRPV1 mRNA and protein have been found in the central amygdale (Zschenderlein et al, 2011;Ramírez-Barrantes et al, 2016), and that there is evidence for physiologic and pharmacological interactions between CaMKIIa and TRPV1 receptors (Price et al, 2005;Nakanishi et al, 2010) forming possible feed-forward loops , it is therefore possible that presynaptic CaMKIIa may also be a regulator of fentanyl-induced hyperalgesia.…”

Identification of the Plant Steroid α-Spinasterol as a Novel Transient Receptor Potential Vanilloid 1 Antagonist with Antinociceptive Properties

“…Next, we assessed whether drug-induced antinociception could still be detected in RTX-treated mice. We chose morphine because it may induce antinociception in TRPV1 knockout mice (Vardanyan et al, 2009) and RTXtreated rats (Chen and Pan, 2006). Unlike ␣-spinasterol and SB-366791, the antinociceptive effect produced by morphine was observed in both vehicle-and RTX-treated mice, indicating that ablation of positive TRPV1 fibers by RTX treatment is capable of decreasing only TRPV1-mediated antinociception.…”