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. 2021 May;22(5):498-508.
doi: 10.1016/j.jpain.2020.11.004. Epub 2020 Nov 21.

Involvement of TACAN, a Mechanotransducing Ion Channel, in Inflammatory But Not Neuropathic Hyperalgesia in the Rat

Ivan J M Bonet  1 , Dionéia Araldi  1 , Oliver Bogen  1 , Jon D Levine  2
Affiliations

Involvement of TACAN, a Mechanotransducing Ion Channel, in Inflammatory But Not Neuropathic Hyperalgesia in the Rat

Ivan J M Bonet et al. J Pain. 2021 May.

Abstract

TACAN (Tmem120A), a mechanotransducing ion channel highly expressed in a subset of nociceptors, has recently been shown to contribute to detection of noxious mechanical stimulation. In the present study we evaluated its role in sensitization to mechanical stimuli associated with preclinical models of inflammatory and chemotherapy-induced neuropathic pain (CIPN). Intrathecal administration of an oligodeoxynucleotide antisense (AS-ODN) to TACAN mRNA attenuated TACAN protein expression in rat dorsal root ganglia (DRG). While TACAN AS-ODN produced only a modest increase in mechanical nociceptive threshold, it markedly reduced mechanical hyperalgesia produced by intradermal administration of prostaglandin E2, tumor necrosis factor alpha, and low molecular weight hyaluronan, and systemic administration of lipopolysaccharide, compatible with a prominent role of TACAN in mechanical hyperalgesia produced by inflammation. In contrast, TACAN AS-ODN had no effect on mechanical hyperalgesia associated with CIPN produced by oxaliplatin or paclitaxel. Our results provide evidence that TACAN plays a role in mechanical hyperalgesia induced by pronociceptive inflammatory mediators, but not CIPN, compatible with multiple mechanisms mediating mechanical nociception, and sensitization to mechanical stimuli in preclinical models of inflammatory versus CIPN. PERSPECTIVE: We evaluated the role of TACAN, a mechanotransducing ion channel in nociceptors, in preclinical models of inflammatory and CIPN. Attenuation of TACAN expression reduced hyperalgesia produced by inflammatory mediators but had not chemotherapeutic agents. Our findings support the presence of multiple mechanotransducers in nociceptors.

Keywords: CIPN; TACAN; hyperalgesia; mechanical nociceptive threshold.

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Figures

Figure 1.
Figure 1.. Increase in mechanical nociceptive threshold in rats treated with ODN antisense to TACAN mRNA.
A. Rats were treated intrathecally with AS-ODN (120 μg/20 μL) or MM-ODN (120 μg/20 μL) for TACAN mRNA, once a day for three consecutive days. Mechanical nociceptive threshold was evaluated before the 1st intrathecal administration of AS- or MM-ODN and on days 1, 2, 3, 4, 5, 8, 11 and 14 after its last administration. The group that received TACAN AS-ODN showed an increase in mechanical nociceptive threshold (g) that persisted until 5 days after the last injection (F(8,80)=9.219, *p=0.0229 when the TACAN AS-ODN- is compared with the TACAN MM- ODN-treated group; two-way repeated-measures ANOVA followed by Bonferroni’s multiple comparison test). Data in all figures are presented as values for individual animals._n=6 per group. B. Western blot analysis of DRG extracts from rats injected with 120 μg of antisense ODN/day for three consecutive days revealed a significant decrease in anti-Tmem120A immunoreactivity when compared with the extracts of DRG from mismatch treated rats (−35.6 ± 14.6%, t(10)=2.438; *p=0.0175 unpaired student’s t-test). The calculated molecular weight of Tmem120A in rat tissue is ~41 kDa (according to UniProtKB database entry Q5HZE2). PKCε, which was used as loading control, has a calculated molecular weight of ~84 kDa (according to UniProtKB database entry P09216). n=6 per group.
Figure 2.
Figure 2.. TACAN AS-ODN attenuates mechanical hyperalgesia induced by pronociceptive inflammatory mediators.
A. Rats were treated intrathecally with AS- (120 μg/20 μL) or MM- (120 μg/20 μL) ODN for TACAN mRNA, once a day for three consecutive days. On the fourth day, approximately 24 h after the last intrathecal administration of ODNs, when the mechanical nociceptive threshold was significantly elevated from pre-ODN baseline, in the TACAN AS-ODN-treated group (t(5)=1.000; p=0.3632, for the TACAN MM-ODN-treated group and, t(5)=7.000; ###p=0.0009, for the TACAN AS-ODN-treated group, when the mechanical nociceptive threshold is compared before and approximately 24 hours after the third intrathecal injection of ODNs; paired Student’s t-test), PGE2 (100 ng/5 μL) was injected intradermally on the dorsum of the hind paw. The mechanical nociceptive threshold was again evaluated 10, 30 and 60 min after PGE2. The group that received TACAN AS-ODN showed a decrease in PGE2-induced hyperalgesia when compared to the TACAN MM-ODN-treated group (F(4,40)=10.80, **p=0.0069, when the TACAN AS-ODN-treated group is compared with TACAN MM-ODN-treated group, before intradermal PGE2; **p=0.0033, when the TACAN AS-ODN- is compared with TACAN MM-ODN-treated group 10, 30 and 60 min after PGE2; two-way repeated-measures ANOVA followed by Bonferroni’s multiple comparison test). n=6 per group. B. Rats were treated intrathecally with TACAN AS- (120 μg/20 μL) or MM- (120 μg/20 μL) ODN, once a day, for three consecutive days. On the fourth day, approximately 24 h after the last intrathecal administration of ODN, when the mechanical nociceptive threshold was significantly elevated compared to pre-ODN baseline in the TACAN AS-ODN-treated group (t(5) = 2.072; p=0.0930, for the TACAN MM-ODN-treated group and, t(5)=10.07; ###p=0.0002, for the TACAN AS-ODN-treated group, when the mechanical nociceptive threshold is compared before and approximately 24 hours after the third intrathecal injection of ODNs; paired Student’s t-test), TNFα (100 ng/5 μL) was injected intradermally on the dorsum of the hind paw. The mechanical nociceptive threshold was again evaluated 10, 30 and 60 min after TNFα. In the group that received TACAN AS-ODN, TNFα-induced hyperalgesia was significantly inhibited compared to the TACAN MM-ODN-treated group, 30 and 60 min after TNFα (F(4,40)=38.61, ***p=0.0004, when the TACAN AS-ODN-treated group is compared with TACAN MM-ODN-treated group, before intradermal TNFα; ****p<0.0001 when the TACAN AS-ODN- is compared with TACAN MM-ODN-treated group 30 and 60 min after TNFα; two-way repeated-measures ANOVA followed by Bonferroni’s multiple comparison test). n=6 per group.
Figure 3.
Figure 3.. TACAN AS-ODN attenuates LMWH-induced mechanical hyperalgesia.
Rats were treated intrathecally with TACAN AS- (120 μg/20 μL) or MM- (120 μg/20 μL) ODN, once a day, for three consecutive days. On the fourth day, approximately 24 h after the last intrathecal administration of ODN, when the mechanical nociceptive threshold was significantly elevated from pre-ODN baseline in the TACAN AS-ODN-treated group (t(5) = 2.340; p=0.0664, for the TACAN MM-ODN-treated group and, t(5)=6.379; ##p=0.0014, for the TACAN AS-ODN-treated group, when the mechanical nociceptive threshold is compared before and approximately 24 hours after the third intrathecal injection of ODNs; paired Student’s t-test), LMWH (1 μg/5 μL) was injected intradermally on the dorsum of the hind paw. Mechanical nociceptive threshold was evaluated 5, 10, 15, 20 and 30 min after LMWH. In the group that received TACAN AS-ODN, hyperalgesia induced by LMWH was markedly attenuated 15, 20 and 30 min after LMWH, when compared with the TACAN MM-ODN- treated group (F(6,60)=5.828, **p<0.0085, when the TACAN AS-ODN- is compared with TACAN MM-ODN-treated group before intradermal LMWH; ***p=0.0002 when the TACAN AS-ODN- is compared with TACAN MM-ODN-treated group 15, 20 and 30 min after LMWH; two-way repeated-measures ANOVA followed by Bonferroni’s multiple comparison test). n=6 per group.
Figure 4.
Figure 4.. TACAN AS-ODN attenuates LPS-induced mechanical hyperalgesia.
TACAN AS- (120 μg/20 μL) or MM- (120 μg/20 μL) ODN was administered intrathecally in rats, once a day, for three consecutive days. On the fourth day, approximately 24 h after the last intrathecal administration of AS-ODN, when the mechanical nociceptive threshold was significantly elevated from pre-ODN baseline in the TACAN AS-ODN-treated group (t(5)=1.291; p=0.2532, for the TACAN MM-ODN-treated group and, t(5)=5.534; ##p=0.0026, for the TACAN AS-ODN-treated group, when the mechanical nociceptive threshold is compared before and approximately 24 hours after the third intrathecal injection of ODNs; paired Student’s t-test), LPS (100 μg/kg) was injected intraperitoneally (i.p.). The mechanical nociceptive threshold was evaluated 1 h and 1, 2, 5 and 8 days after LPS. In the group that received TACAN AS-ODN, mechanical hyperalgesia induced by systemic LPS was robustly attenuated 1 hour after its i.p. administration, and still attenuated a 1, 2, and 5 days later, compared with the TACAN MM-ODN-treated group (F(6,60)=21.25; ***p<0.0009, when the TACAN AS-ODN- is compared with the TACAN MM-ODN-treated group before intraperitoneal LPS; ****p<0.0001 1 h and 1 and 2 day after intraperitoneal LPS: **p=0.0020; 5 days after intraperitoneal LPS; when the TACAN AS-ODN- is compared with TACAN MM-ODN-treated group; two-way repeated-measures ANOVA followed by Bonferroni’s multiple comparison test). Eight days after i.p. LPS there was no difference between the TACAN AS- and MM-ODN-treated groups. n=6 per group.
Figure 5.
Figure 5.. TACAN AS-ODN does not attenuate mechanical hyperalgesia associated with oxaliplatin chemotherapy-induced peripheral neuropathy (CIPN).
Rats were treated intrathecally with TACAN AS- (120 μg/20 μL) or MM- (120 μg/20 μL) ODN, once a day, for three consecutive days. On the fourth day, approximately 24 h after the last intrathecal administration of ODNs, (t(5)=0.5218; p=0.6241, for the TACAN MM- ODN-treated group and, t(5)=7.593; ###p=0.0006, for the TACAN AS-ODN-treated group, when the mechanical nociceptive threshold is compared before and approximately 24 hours after the third intrathecal injection of ODN; paired Student’s t-test), rats received an intravenous injection of oxaliplatin (2 mg/kg). The mechanical nociceptive threshold was evaluated before the 1st dose of ODNs, before oxaliplatin injection, and then 30min and 1, 7 14, 21 and 28 days after oxaliplatin. TACAN AS-ODN did not attenuate oxaliplatin-induced mechanical hyperalgesia at any time point evaluated (F(7,70)=5.874, *p<0.0136, when the TACAN AS-ODN- is compared with TACAN MM-ODN-treated group before intravenous oxaliplatin; p=0.5868 when the TACAN AS-ODN- is compared with TACAN MM-ODN-treated group after oxaliplatin; two-way repeated-measures ANOVA followed by Bonferroni’s multiple comparison test). n=6 per group.
Figure 6.
Figure 6.. TACAN AS-ODN does not attenuate mechanical hyperalgesia associated with paclitaxel chemotherapy-induced peripheral neuropathy (CIPN).
TACAN AS- (120 μg/20 μL) or MM- (120 μg/20 μL) ODN was administered to rats, once a day for three consecutive days. On the fourth day, approximately 24 h after the third intrathecal administration of ODN (t(5)= 0.7906; p=0. 4650, for the TACAN MM-ODN- treated group and, t(5)=18.49; ####p<0.0001, for the TACAN AS-ODN-treated group, when the mechanical nociceptive threshold is compared before and approximately 24 hours after the third intrathecal injection of ODNs; paired Student’s t-test), paclitaxel (1 mg/kg) was administered intraperitoneally, every other day for a total of 4 doses (days 0, 2, 4 and 6). TACAN AS- and MM-ODNs were also administered every other day, after the third consecutive daily intrathecal administration, until day 6 after paclitaxel (total of 6 doses). Mechanical nociceptive threshold was evaluated before the first dose of ODNs, before the first dose of paclitaxel, and then, on days 1, 7, 14, 21 and 28 after the first dose of paclitaxel. TACAN AS-ODN did not attenuate paclitaxel-induced mechanical hyperalgesia at any time point (F(5,50)=17.02, ****p<0.0001, when the TACAN AS-ODN- is compared with TACAN MM- ODN-treated group before intraperitoneal paclitaxel; p=0.6081 when the TACAN AS-ODN- is compared with TACAN MM-ODN-treated group; two-way repeated-measures ANOVA followed by Bonferroni’s multiple comparison test). n=6 per group.
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