Long-Term Blockade of Nociceptive Na<sub>v</sub>1.7 Channels Is Analgesic in Rat Models of Knee Arthritis
The voltage gated sodium channels (Na<sub>v</sub>) 1.7, 1.8, and 1.9 are primarily located on nociceptors where they are involved in signalling neuropathic pain. This study examined the effect of Na<sub>v</sub>1.7 blockade on joint pain using either the small molecule inhibit...
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MDPI AG
2022-10-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/12/11/1571 |
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| author | Allison R. Reid Patrice D. Côté Jason J. McDougall |
| author_facet | Allison R. Reid Patrice D. Côté Jason J. McDougall |
| author_sort | Allison R. Reid |
| collection | DOAJ |
| description | The voltage gated sodium channels (Na<sub>v</sub>) 1.7, 1.8, and 1.9 are primarily located on nociceptors where they are involved in signalling neuropathic pain. This study examined the effect of Na<sub>v</sub>1.7 blockade on joint pain using either the small molecule inhibitor PF05089771 or an antibody directed towards the intracellular domain of the ion channel. Male Wistar rats were assigned to one of three experimental groups consisting of either intra-articular injection of 3 mg sodium monoiodoacetate (MIA—joint degeneration group), intra-articular injection of 100 μg lysophosphatidic acid (LPA—joint neuropathy group), or transection of the medial meniscus (MMT—posttraumatic osteoarthritis group). G-ratio calculations were performed to determine potential demyelination and immunohistochemistry was used to measure Na<sub>v</sub>1.7 expression on joint afferent cell bodies. Pain behaviour was evaluated over 3 h by von Frey hair algesiometry and hindlimb weight bearing before and after local administration of PF05089771 (0.1 mg/50 µL). Chronic pain behaviour was assessed over 28 days following peripheral treatment with a Na<sub>v</sub>1.7 antibody (Ab) in conjunction with the transmembrane carrier peptide Pep1. Demyelination and increased Na<sub>v</sub>1.7 channel expression were observed in MIA and LPA rats, but not with MMT. Acute secondary allodynia was diminished by PF05089771 while a single injection of Na<sub>v</sub>1.7 Ab-Pep1 reduced pain up to 28 days. This analgesia only occurred in MIA and LPA animals. Hindlimb incapacitance was not affected by any treatment. These data indicate that joint pain associated with neural demyelination can be alleviated somewhat by Na<sub>v</sub>1.7 channel blockade. Biologics that inactivate Na<sub>v</sub>1.7 channels have the potential to reduce arthritis pain over a protracted period of time. |
| first_indexed | 2024-03-09T19:14:38Z |
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| language | English |
| last_indexed | 2024-03-09T19:14:38Z |
| publishDate | 2022-10-01 |
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| series | Biomolecules |
| spelling | doaj.art-db913d02dadc491e9f0a048246c858062023-11-24T03:52:48ZengMDPI AGBiomolecules2218-273X2022-10-011211157110.3390/biom12111571Long-Term Blockade of Nociceptive Na<sub>v</sub>1.7 Channels Is Analgesic in Rat Models of Knee ArthritisAllison R. Reid0Patrice D. Côté1Jason J. McDougall2Departments of Pharmacology and Anaesthesia, Pain Management & Perioperative Medicine, Dalhousie University, 5850 College Street, Halifax, NS B3H 4R2, CanadaDepartment of Biology, Dalhousie University, 1355 Oxford, Halifax, NS B3H 4R2, CanadaDepartments of Pharmacology and Anaesthesia, Pain Management & Perioperative Medicine, Dalhousie University, 5850 College Street, Halifax, NS B3H 4R2, CanadaThe voltage gated sodium channels (Na<sub>v</sub>) 1.7, 1.8, and 1.9 are primarily located on nociceptors where they are involved in signalling neuropathic pain. This study examined the effect of Na<sub>v</sub>1.7 blockade on joint pain using either the small molecule inhibitor PF05089771 or an antibody directed towards the intracellular domain of the ion channel. Male Wistar rats were assigned to one of three experimental groups consisting of either intra-articular injection of 3 mg sodium monoiodoacetate (MIA—joint degeneration group), intra-articular injection of 100 μg lysophosphatidic acid (LPA—joint neuropathy group), or transection of the medial meniscus (MMT—posttraumatic osteoarthritis group). G-ratio calculations were performed to determine potential demyelination and immunohistochemistry was used to measure Na<sub>v</sub>1.7 expression on joint afferent cell bodies. Pain behaviour was evaluated over 3 h by von Frey hair algesiometry and hindlimb weight bearing before and after local administration of PF05089771 (0.1 mg/50 µL). Chronic pain behaviour was assessed over 28 days following peripheral treatment with a Na<sub>v</sub>1.7 antibody (Ab) in conjunction with the transmembrane carrier peptide Pep1. Demyelination and increased Na<sub>v</sub>1.7 channel expression were observed in MIA and LPA rats, but not with MMT. Acute secondary allodynia was diminished by PF05089771 while a single injection of Na<sub>v</sub>1.7 Ab-Pep1 reduced pain up to 28 days. This analgesia only occurred in MIA and LPA animals. Hindlimb incapacitance was not affected by any treatment. These data indicate that joint pain associated with neural demyelination can be alleviated somewhat by Na<sub>v</sub>1.7 channel blockade. Biologics that inactivate Na<sub>v</sub>1.7 channels have the potential to reduce arthritis pain over a protracted period of time.https://www.mdpi.com/2218-273X/12/11/1571Arthritisbiologicsdemyelinationneuropathic painvoltage-gated sodium channels |
| spellingShingle | Allison R. Reid Patrice D. Côté Jason J. McDougall Long-Term Blockade of Nociceptive Na<sub>v</sub>1.7 Channels Is Analgesic in Rat Models of Knee Arthritis Biomolecules Arthritis biologics demyelination neuropathic pain voltage-gated sodium channels |
| title | Long-Term Blockade of Nociceptive Na<sub>v</sub>1.7 Channels Is Analgesic in Rat Models of Knee Arthritis |
| title_full | Long-Term Blockade of Nociceptive Na<sub>v</sub>1.7 Channels Is Analgesic in Rat Models of Knee Arthritis |
| title_fullStr | Long-Term Blockade of Nociceptive Na<sub>v</sub>1.7 Channels Is Analgesic in Rat Models of Knee Arthritis |
| title_full_unstemmed | Long-Term Blockade of Nociceptive Na<sub>v</sub>1.7 Channels Is Analgesic in Rat Models of Knee Arthritis |
| title_short | Long-Term Blockade of Nociceptive Na<sub>v</sub>1.7 Channels Is Analgesic in Rat Models of Knee Arthritis |
| title_sort | long term blockade of nociceptive na sub v sub 1 7 channels is analgesic in rat models of knee arthritis |
| topic | Arthritis biologics demyelination neuropathic pain voltage-gated sodium channels |
| url | https://www.mdpi.com/2218-273X/12/11/1571 |
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