Armadillo regulates nociceptive sensitivity in the absence of injury

Abstract

Abnormal pain has recently been estimated to affect ∼50 million adults each year within the United States. With many treatment options for abnormal pain, such as opioid analgesics, carrying numerous deleterious side effects, research into safer and more effective treatment options is crucial. To help elucidate the mechanisms controlling nociceptive sensitivity, the <i>Drosophila melanogaster</i> larval nociception model has been used to characterize well-conserved pathways through the use of genetic modification and/or injury to alter the sensitivity of experimental animals. Mammalian models have provided evidence of β-catenin signaling involvement in neuropathic pain development. By capitalizing on the conserved nature of β-catenin functions in the fruit fly, here we describe a role for Armadillo, the fly homolog to mammalian β-catenin, in regulating baseline sensitivity in the primary nociceptor of the fly, in the absence of injury, using under- and over-expression of Armadillo in a cell-specific manner. Underexpression of Armadillo resulted in hyposensitivity, while overexpression of wild-type Armadillo or expression of a degradation-resistant Armadillo resulted in hypersensitivity. Neither underexpression nor overexpression of Armadillo resulted in dendritic morphological changes that could contribute to behavioral phenotypes observed. These results showed that focused manipulation of Armadillo expression within the nociceptors is sufficient to modulate baseline response in the nociceptors to a noxious stimulus and that these changes are not shown to be associated with a morphogenetic effect.

The Primary Cilium and its Hedgehog Signaling in Nociceptors Contribute to Inflammatory and Neuropathic Pain

“…WNT agonists directly generate hypernociception 105 ; and, Wnt3a recruits Wnt-calcium signaling in sensory neurons to enhance pain sensitivity 104,106 . Importantly, in contrast to Shh signaling, the fly homolog of b-catenin, Armadillo, does regulate baseline sensitivity in nociceptors, in the absence of injury or inflammation 91 . However, studies in species, in addition to Drosophila, and establishing whether this function of Wnt/b-catenin signaling in nociceptor function is primary cilium dependent, and the mechanism by which it controls nociceptive threshold, remains to be established.…”

“…Of note, however, in contrast to the effect of Ift88 siRNA in control rats, which increased baseline mechanical nociceptive threshold in naïve control rats, inhibitors of Hh signaling in the absence of inflammation or peripheral neuropathy did not affect nociceptive threshold, supporting the presence of an Hh-independent primary cilium function capable of regulating baseline mechanical nociceptive threshold. Another primary cilium-dependent cellular signaling pathway that has been found to contribute to nociception is the wingless-related integration site (Wnt)/b-catenin signaling pathway [89][90][91][92][93][94][95] . Ciliary proteins are not only necessary for the regulation of certain types of Wnt signaling but also include effectors downstream of Wnt [96][97][98][99] .…”

The Primary Cilium and its Hedgehog Signaling in Nociceptors Contribute to Inflammatory and Neuropathic Pain

“…Of note, however, in contrast to the effect of Ift88 siRNA in control rats, which increased baseline mechanical nociceptive threshold in naïve control rats, inhibitors of Hh signaling in the absence of inflammation or peripheral neuropathy did not affect nociceptive threshold, supporting the presence of an Hh-independent primary cilium function capable of regulating baseline mechanical nociceptive threshold. Another primary cilium-dependent cellular signaling pathway that has been found to contribute to nociception is the wingless-related integration site (Wnt)/b-catenin signaling pathway [89][90][91][92][93][94][95] . Ciliary proteins are not only necessary for the regulation of certain types of Wnt signaling but also include effectors downstream of Wnt .…”