Colocalization of insulin-like growth factor-1 receptor and T type Cav3.2 channel in dorsal root ganglia in chronic inflammatory pain mouse model

Abstract

Insulin-like growth factor-1 (IGF-1) is a neurotrophic factor and plays important roles in the nervous system. Increasing evidence supports that IGF-1 contributes to pain hypersensitivity through its insulin-like growth factor-1 receptor (IGF-1R) by activating IGF-1R/Akt or MAPK signaling pathways, whereas T-type Cav3.2 channel can facilitate and amplify pain signals originating from the sensory periphery. A recent study showed that activated IGF-1R can increase T-type Cav3.2 channel currents and further activate the G protein-dependent PKCα pathway to contribute to inflammatory pain sensitivity. However, the colocalization of IGF-1R and Cav3.2 in mouse dorsal root ganglion (DRG) under chronic inflammatory pain conditions remains elusive. In this study, we investigated changes in the expression of IGF-1R and the Cav3.2 channel, and their colocalization in mouse DRGs in chronic inflammatory pain condition (induced by complete Freund's adjuvant intraplanter injection) using real-time RT-PCR and immunohistochemistry approaches to confirm that Cav3.2 channel can mediate pain facilitation following IGF-1/IGF-1R signaling. We found that IGF-1R was expressed extensively in DRG neurons including small-, medium-, and large-sized neurons, whereas Cav3.2 channel was expressed exclusively in small-sized DRG neurons of naive mice. Expression of Cav3.2, but not IGF-1R, and colocalization of Cav3.2 and IGF-1R were increased in lumbar (L)4-L6 primary sensory neurons in DRGs of mice in chronic inflammatory pain. Moreover, the increased colocalization of IGF-1R and Cav3.2 is exclusively localized in small- and medium-sized primary sensory neurons. Our findings provided morphological evidence that T-type Cav3.2 channel, at least partially, mediates the pain facilitation of IGF-1/IGF-1R signaling in chronic inflammatory pain condition.

Macrophage‐derived insulin‐like growth factor‐1 is a key neurotrophic and nerve‐sensitizing factor in pain associated with endometriosis

“…There is increasing evidence that Igf-1 contributes to pain hypersensitivity through binding to Igf-1r and activating Igf-1r–mediated PI3K, ERK, protein kinase B, or MAPK intracellular signaling pathways (53). Igf-1r is widely expressed in small, medium, and large DRG neurons (37, 54), and in chronic inflammatory and tissue injury models, Igf-1 signaling enhances thermal and mechanical hyperalgesia (54, 55). Moreover, inhibition of Igf-1r can reverse mechanical allodynia and thermal hyperalgesia in a rat model of cancer bone pain (36).…”

Increase in IGF-1 Expression in the Injured Infraorbital Nerve and Possible Implications for Orofacial Neuropathic Pain

“…Besides, IGF-1 does not only bind to TRPV2 channels but also to IGF-I receptors which are predominantly expressed in nociceptive neurons of sensory ganglia [36]. It has been reported that IGF-1 signaling via IGF-I receptors promotes the translocation of TRPV2 from intracellular pools towards the plasma membrane via phosphoinositide 3 (PI3) kinase activation in vitro; IGF-1-evoked Ca 2+ entry is consequently caused by TRPV2 activation [12,33,37].…”

Histone methylation-mediated microRNA-32-5p down-regulation in sensory neurons regulates pain behaviors via targeting Cav3.2 channels

“…This expression pattern is consistent with previous data showing abundant expression of Cav3.2 channels in small- to medium-sized TG neurons ( 25 , 41 ), while distinct from the broader distribution of Cav3.2 in rat DRG neurons ( 42 ). Cav3.2 channels were reported to be expressed exclusively in small DRG neurons in naïve mice ( 43 , 44 ); however, these results seem to be contradictory to those of most related studies. Increased expression of Cav3 isoform T-type channels in sensory neurons has shown functional diversity in distinct pain disorders ( 23 , 45 , 46 ).…”