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. 2019 Dec 17;20(24):6360.
doi: 10.3390/ijms20246360.

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

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Free PMC article

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

Shiori Sugawara et al. Int J Mol Sci. .
Free PMC article

Abstract

Insulin-like growth factor-1 (IGF-1) is upregulated in the injured peripheral nerve bundle and controls nociceptive neuronal excitability associated with peripheral nerve injury. Here, we examined the involvement of IGF-1 signaling in orofacial neuropathic pain following infraorbital nerve injury (IONI) in rats. IONI promoted macrophage accumulation in the injured ION, as well as in the ipsilateral trigeminal ganglion (TG), and induced mechanical allodynia of the whisker pad skin together with the enhancement of neuronal activities in the subnucleus caudalis of the spinal trigeminal nucleus and in the upper cervical spinal cord. The levels of IGF-1 released by infiltrating macrophages into the injured ION and the TG were significantly increased. The IONI-induced the number of transient receptor potential vanilloid (TRPV) subfamily type 4 (TRPV4) upregulation in TRPV subfamily type 2 (TRPV2)-positive small-sized, and medium-sized TG neurons were inhibited by peripheral TRPV2 antagonism. Furthermore, the IONI-induced mechanical allodynia was suppressed by TRPV4 antagonism in the whisker pad skin. These results suggest that IGF-1 released by macrophages accumulating in the injured ION binds to TRPV2, which increases TRPV4 expression in TG neurons innervating the whisker pad skin, ultimately resulting in mechanical allodynia of the whisker pad skin.

Keywords: macrophage; mechanical allodynia; transient receptor potential channels vanilloid subfamily type 2; transient receptor potential channels vanilloid subfamily type 4; trigeminal ganglion; trigeminal nerve injury; upper cervical spinal cord.

Conflict of interest statement

The authors no conflict of interest.

Figures

Figure 1
Figure 1
Changes in mechanical head withdrawal threshold of the whisker pad skin following sham treatment or IONI. Sham, sham treatment with vehicle administration; IONI-vehicle, IONI with vehicle administration; IONI-Tranilast: IONI with tranilast administration (n = 5 in each group). The box bottom and top indicate the lower and upper quartiles, respectively. The lower and upper whiskers represent the minimum and maximum values, respectively. * p < 0.05, † p < 0.01, ‡ p < 0.001 (vs IONI-vehicle group). IONI, infraorbital nerve injury.
Figure 2
Figure 2
Activities of single WDR neurons in the upper cervical spinal cord on day 3. Peristimulus time histograms of WDR neurons in response to mechanical stimulation of the whisker pad skin and their BG activity on day 3 following sham treatment or IONI with or without tranilast administration (A). Mean spike frequencies of WDR neurons in response to graded mechanical stimulation of the whisker pad skin (B), no stimulation (C), and brush (D) or pinch (E) stimulation on day 3 following sham treatment and or IONI with vehicle or tranilast administration. ** p < 0.01, *** p < 0.001, **** p < 0.0001 (vs sham group). WDR, wide dynamic range; BG, background; IONI, infraorbital nerve injury.
Figure 3
Figure 3
Peripheral IGF-1 expression following sham treatment or IONI. IGF-1 expression in Iba1- or GFAP-IR cells and the mean relative density of Iba1-IR cells in the injured ION on day 3 following IONI and sham treatment (A). Arrows indicate IGF-1- and Iba1-IR cells. Scale bar: 100 µm. ** p < 0.01 (vs sham treatment group). (n = 3 in each group). The amount of IGF-1 protein in the injured ION on day 3 and day 7 following sham treatment or IONI (B). The loading control was β-actin. *** p < 0.01 (vs sham treatment group; day 3, n = 9 in each group; day 7, n = 6 in each group). IGF-1 expression in Iba1-IR or GFAP-IR cells and the mean relative density of Iba1-IR cells in the TG on day 3 following IONI and sham treatment (C). Arrows indicate IGF-1- and Iba1-IR cells. Scale bar: 50 µm. * p < 0.05 (vs sham treatment group; n = 3 in each group). The amount of IGF-1 protein in the TG on day 3 and day 7 following sham treatment or IONI (D). The loading control was β-actin. * p < 0.05 (vs sham treatment group; day 3, n = 6 in sham group, n = 5 in IONI group; day 7, n = 6 in each group). IGF-1, insulin-like growth factor-1; IONI, infraorbital nerve injury; GFAP, glial fibrillary acidic protein; IR, immunoreactive; TG, trigeminal ganglion.
Figure 4
Figure 4
Changes in TRPV2 and TRPV4 expression in TG neurons and mechanical sensitivity due to TRPV4 antagonism on day 3 following IONI. TRPV2- and TRPV4-IR TG neurons innervating the whisker pad skin on day 3 following sham treatment or IONI with vehicle or tranilast administration (A). Arrows indicate FG-labeled TRPV2- and TRPV4-IR neurons. Scale bar: 50 µm. Mean percentages of FG-labeled TG neurons (upper) and FG-labeled TRPV2-IR TG neurons (lower) (B), mean percentages of FG labeled TRPV2- and TRPV4-IR TG neurons in FG-labeled TRPV2-IR TG neurons (C), and size-frequency histogram illustrating the distribution of TRPV2- and TRPV4-IR TG neurons (D) on day 3 following sham treatment or IONI with vehicle or tranilast administration. (n = 7 in each group). * p < 0.05, ** p < 0.01 (vs sham treatment group). (E) MHWTs of the whisker pad skin before and on day 3 following IONI with vehicle or HC-067047 administration to the whisker pad skin. The box bottom and top indicate lower and upper quartiles, respectively. The lower and upper whiskers represent the minimum and maximum values, respectively. (n = 5 in each group). * p < 0.05 (vs IONI-vehicle group). TRPV, transient receptor potential vanilloid subfamily; TG, trigeminal ganglion; IONI, infraorbital nerve injury; IR, immunoreactive; FG, FluoroGold; MHWT, mechanical head withdrawal threshold.
Figure 5
Figure 5
Changes in mechanical head withdrawal threshold of the whisker pad skin following sham treatment or IONI. Sham-normal IgG, sham treatment with normal IgG administration; IONI-normal IgG, IONI with normal IgG administration; IONI-anti IGF-1, IONI with IGF-1 neutralizing antibody administration (n = 5 in each group). The boxes bottom and top indicate the lower and upper quartiles, respectively. The lower and upper whiskers represent the minimum and maximum values, respectively. * p < 0.05, † p < 0.01, ‡ p < 0.001 (vs IONI-normal IgG group). IONI, infraorbital nerve injury.

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