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α9-nicotinic acetylcholine receptors contribute to the maintenance of chronic mechanical hyperalgesia, but not thermal or mechanical allodynia.

Mohammadi S, Christie MJ - Mol Pain (2014)

Bottom Line: The first analgesic drug approved for clinical use in decades that has a novel molecular target is the synthetic version of a naturally occurring conotoxin.However, KO animals developed mechanical hyperalgesia to a lesser extent than their wild type (WT) counterparts in both inflammatory and neuropathic pain models.The α9-nAChR is not involved in acute pain perception or chronic thermal or mechanical allodynia or thermal hyperalgesia but does contribute to the intensity and duration of chronic mechanical hyperalgesia, suggesting that pain-relieving actions of antagonists that target this site may be restricted to high threshold mechanosensation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, The University of Sydney, Sydney, NSW, Australia. mac.christie@sydney.edu.au.

ABSTRACT

Background: The current pharmacological treatments for chronic pain are limited. The first analgesic drug approved for clinical use in decades that has a novel molecular target is the synthetic version of a naturally occurring conotoxin. Several conotoxins that target ion channels have progressed to clinical trials for the relief of pain. Vc1.1 and RgIA are analgesic α-conotoxins that target α9-subunit-containing nicotinic acetylcholine receptors (α9-nAChR) as well as GABAB receptor mechanisms. However, the evidence for the involvement of α9-nAChRs in pain is controversial. In the present study, the role of the α9-nAChR in pain was assessed using a battery of behavioural pain tests and pain models in α9-nAChR knockout (KO) mice.

Results: α9-nAChR KO mice showed normal responses to acute noxious thermal and mechanical stimuli, and developed normal chronic cold and mechanical allodynia in inflammatory and nerve injury pain models. However, KO animals developed mechanical hyperalgesia to a lesser extent than their wild type (WT) counterparts in both inflammatory and neuropathic pain models. Chronic neuropathic pain is sustained in WT mice for at least 21 days post injury, while KO mice show significant recovery by 14 days post injury. KO sham mice were also resistant to the repeated-measures effect of the noxious pain test that caused a gradual onset of mild mechanical hyperalgesia in WT sham animals.

Conclusions: The α9-nAChR is not involved in acute pain perception or chronic thermal or mechanical allodynia or thermal hyperalgesia but does contribute to the intensity and duration of chronic mechanical hyperalgesia, suggesting that pain-relieving actions of antagonists that target this site may be restricted to high threshold mechanosensation. The α9-nAChR appears to be a valid target for pharmacological compounds that alleviate long-term mechanical hyperalgesia and may be of use as a prophylactic drug to prevent the development of some symptoms of chronic pain.

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Chronic mechanical hyperalgesia is reduced in α9-nAChR KO mice. Inflammatory (A) and neuropathic (B) pain models produce chronic mechanical allodynia in both WT and KO animals. However, the magnitude of hyperalgesia is less in α9-nAChR KO animals. α9-nAChR KO animals recover from CCI by 14 days post injury (B i) and are resistant to the repeated-measures induced hyperalgesia of the paw pressure test seen in WT animals (B ii). ##, p < 0.01; ###, p < 0.001; ####, p < 0.0001 compared to baseline. *, p < 0.01; **, p < 0.01; ***, p < 0.001 compared to WT.
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Fig4: Chronic mechanical hyperalgesia is reduced in α9-nAChR KO mice. Inflammatory (A) and neuropathic (B) pain models produce chronic mechanical allodynia in both WT and KO animals. However, the magnitude of hyperalgesia is less in α9-nAChR KO animals. α9-nAChR KO animals recover from CCI by 14 days post injury (B i) and are resistant to the repeated-measures induced hyperalgesia of the paw pressure test seen in WT animals (B ii). ##, p < 0.01; ###, p < 0.001; ####, p < 0.0001 compared to baseline. *, p < 0.01; **, p < 0.01; ***, p < 0.001 compared to WT.

Mentions: Chronic mechanical allodynia developed normally in α9-nAChR KO mice. Inflammatory (Figure 3A and C) and neuropathic (Figure 3B and D) pain models both induced mechanical allodynia as expected. Maximal von Frey responses were reached 4 days after CFA injection (F(1,20) = 875.5, p < 0.0001) and 7 days after CCI (F(1,38) = 75.85, p < 0.0001) compared with control groups. Continuation of testing over a 21-day duration after CCI showed sustained allodynia that did not differ between WT and KO (no significant genotype effect, F(1, 38) = 0.13, P = 0.72), with sustained increased responsiveness to the von Frey test on the injured hind-paw, but not on the contralateral hind-paw over 21 days (Figure 3B). For the incapacitance test L:R ratio of weight bearing on the hind paws remained lowered after CCI but not sham surgery (Figure 3D) and did not differ between WT and KO over 21 days (no significant genotype effect, F(1,24) = 2.79, P = 0.10).Mechanical hyperalgesia developed in both genotypes, however the magnitude of hypersensitivity was less in α9-nAChR KO animals compared to WTs in both inflammatory (significant genotype effect, F(1,42) = 10.35, P = 0.003 using two-way ANOVA; multiple comparisons between WT and KO CFA, P < 0.001) (Figure 4A) and neuropathic (significant genotype effect F(1,39) = 18.14, P = 0.0001 using two-way ANOVA by treatment; multiple comparisons between WT and KO CCI, P = 0.05) (Figure 4B) pain models at 4 and 7 days post injury respectively. Continuation of testing weekly after CCI surgery showed that mechanical hyperalgesia persists in WT mice for at least 21 days (P < 0.0001 for each test day compared to normalised baseline, three-way ANOVA with multiple comparisons and Bonferroni post-hoc test), whereas the KO strain shows significant recovery by 14 days post injury (P < 0.0001 on D7, P < 0.05 at D14 and D21 compared to baseline) (Figure 4B i).The noxious nature of the mechanical stimulus used repeatedly in the paw pressure test induced a mild mechanical hyperalgesia in the sham-operated WT mice, apparent at day 14 (P < 0.01) and day 21 (P < 0.001, three-way ANOVA with multiple comparisons and Bonferroni post-hoc test) (Figure 4B ii). The α9-nAChR KO mouse strain was resistant to this repeated-testing effect (no significant change from baseline for KO animals on all post-injury test days, P > 0.05, three-way ANOVA with multiple comparisons). The decrease in threshold of WT sham mice was not due to a delayed effect of the sham surgery, as separate groups of sham-operated WT and KO mice tested only on post-injury day 21 did not differ and had thresholds comparable to raw baseline scores of sham animals (F(3,42) = 0.98, P = 0.41, one-way ANOVA).Figure 3


α9-nicotinic acetylcholine receptors contribute to the maintenance of chronic mechanical hyperalgesia, but not thermal or mechanical allodynia.

Mohammadi S, Christie MJ - Mol Pain (2014)

Chronic mechanical hyperalgesia is reduced in α9-nAChR KO mice. Inflammatory (A) and neuropathic (B) pain models produce chronic mechanical allodynia in both WT and KO animals. However, the magnitude of hyperalgesia is less in α9-nAChR KO animals. α9-nAChR KO animals recover from CCI by 14 days post injury (B i) and are resistant to the repeated-measures induced hyperalgesia of the paw pressure test seen in WT animals (B ii). ##, p < 0.01; ###, p < 0.001; ####, p < 0.0001 compared to baseline. *, p < 0.01; **, p < 0.01; ***, p < 0.001 compared to WT.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Fig4: Chronic mechanical hyperalgesia is reduced in α9-nAChR KO mice. Inflammatory (A) and neuropathic (B) pain models produce chronic mechanical allodynia in both WT and KO animals. However, the magnitude of hyperalgesia is less in α9-nAChR KO animals. α9-nAChR KO animals recover from CCI by 14 days post injury (B i) and are resistant to the repeated-measures induced hyperalgesia of the paw pressure test seen in WT animals (B ii). ##, p < 0.01; ###, p < 0.001; ####, p < 0.0001 compared to baseline. *, p < 0.01; **, p < 0.01; ***, p < 0.001 compared to WT.
Mentions: Chronic mechanical allodynia developed normally in α9-nAChR KO mice. Inflammatory (Figure 3A and C) and neuropathic (Figure 3B and D) pain models both induced mechanical allodynia as expected. Maximal von Frey responses were reached 4 days after CFA injection (F(1,20) = 875.5, p < 0.0001) and 7 days after CCI (F(1,38) = 75.85, p < 0.0001) compared with control groups. Continuation of testing over a 21-day duration after CCI showed sustained allodynia that did not differ between WT and KO (no significant genotype effect, F(1, 38) = 0.13, P = 0.72), with sustained increased responsiveness to the von Frey test on the injured hind-paw, but not on the contralateral hind-paw over 21 days (Figure 3B). For the incapacitance test L:R ratio of weight bearing on the hind paws remained lowered after CCI but not sham surgery (Figure 3D) and did not differ between WT and KO over 21 days (no significant genotype effect, F(1,24) = 2.79, P = 0.10).Mechanical hyperalgesia developed in both genotypes, however the magnitude of hypersensitivity was less in α9-nAChR KO animals compared to WTs in both inflammatory (significant genotype effect, F(1,42) = 10.35, P = 0.003 using two-way ANOVA; multiple comparisons between WT and KO CFA, P < 0.001) (Figure 4A) and neuropathic (significant genotype effect F(1,39) = 18.14, P = 0.0001 using two-way ANOVA by treatment; multiple comparisons between WT and KO CCI, P = 0.05) (Figure 4B) pain models at 4 and 7 days post injury respectively. Continuation of testing weekly after CCI surgery showed that mechanical hyperalgesia persists in WT mice for at least 21 days (P < 0.0001 for each test day compared to normalised baseline, three-way ANOVA with multiple comparisons and Bonferroni post-hoc test), whereas the KO strain shows significant recovery by 14 days post injury (P < 0.0001 on D7, P < 0.05 at D14 and D21 compared to baseline) (Figure 4B i).The noxious nature of the mechanical stimulus used repeatedly in the paw pressure test induced a mild mechanical hyperalgesia in the sham-operated WT mice, apparent at day 14 (P < 0.01) and day 21 (P < 0.001, three-way ANOVA with multiple comparisons and Bonferroni post-hoc test) (Figure 4B ii). The α9-nAChR KO mouse strain was resistant to this repeated-testing effect (no significant change from baseline for KO animals on all post-injury test days, P > 0.05, three-way ANOVA with multiple comparisons). The decrease in threshold of WT sham mice was not due to a delayed effect of the sham surgery, as separate groups of sham-operated WT and KO mice tested only on post-injury day 21 did not differ and had thresholds comparable to raw baseline scores of sham animals (F(3,42) = 0.98, P = 0.41, one-way ANOVA).Figure 3

Bottom Line: The first analgesic drug approved for clinical use in decades that has a novel molecular target is the synthetic version of a naturally occurring conotoxin.However, KO animals developed mechanical hyperalgesia to a lesser extent than their wild type (WT) counterparts in both inflammatory and neuropathic pain models.The α9-nAChR is not involved in acute pain perception or chronic thermal or mechanical allodynia or thermal hyperalgesia but does contribute to the intensity and duration of chronic mechanical hyperalgesia, suggesting that pain-relieving actions of antagonists that target this site may be restricted to high threshold mechanosensation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, The University of Sydney, Sydney, NSW, Australia. mac.christie@sydney.edu.au.

ABSTRACT

Background: The current pharmacological treatments for chronic pain are limited. The first analgesic drug approved for clinical use in decades that has a novel molecular target is the synthetic version of a naturally occurring conotoxin. Several conotoxins that target ion channels have progressed to clinical trials for the relief of pain. Vc1.1 and RgIA are analgesic α-conotoxins that target α9-subunit-containing nicotinic acetylcholine receptors (α9-nAChR) as well as GABAB receptor mechanisms. However, the evidence for the involvement of α9-nAChRs in pain is controversial. In the present study, the role of the α9-nAChR in pain was assessed using a battery of behavioural pain tests and pain models in α9-nAChR knockout (KO) mice.

Results: α9-nAChR KO mice showed normal responses to acute noxious thermal and mechanical stimuli, and developed normal chronic cold and mechanical allodynia in inflammatory and nerve injury pain models. However, KO animals developed mechanical hyperalgesia to a lesser extent than their wild type (WT) counterparts in both inflammatory and neuropathic pain models. Chronic neuropathic pain is sustained in WT mice for at least 21 days post injury, while KO mice show significant recovery by 14 days post injury. KO sham mice were also resistant to the repeated-measures effect of the noxious pain test that caused a gradual onset of mild mechanical hyperalgesia in WT sham animals.

Conclusions: The α9-nAChR is not involved in acute pain perception or chronic thermal or mechanical allodynia or thermal hyperalgesia but does contribute to the intensity and duration of chronic mechanical hyperalgesia, suggesting that pain-relieving actions of antagonists that target this site may be restricted to high threshold mechanosensation. The α9-nAChR appears to be a valid target for pharmacological compounds that alleviate long-term mechanical hyperalgesia and may be of use as a prophylactic drug to prevent the development of some symptoms of chronic pain.

Show MeSH
Related in: MedlinePlus