TNF-Alpha as an Initiator of Allodynia and Anxiety-Like Behaviors in a Preclinical Model of PTSD and Comorbid Pain
Post-Traumatic Stress Disorder (PTSD) is a debilitating mental health disorder that occurs after exposure to a traumatic event. Patients with comorbid chronic pain experience affective distress, worse quality of life, and poorer responses to treatments for pain or PTSD than those with either conditi...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-08-01
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| Series: | Frontiers in Psychiatry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fpsyt.2021.721999/full |
| _version_ | 1819136234667114496 |
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| author | Patrick Dib Yong Zhang Michael A. Ihnat Michael A. Ihnat Michael A. Ihnat Randle M. Gallucci Randle M. Gallucci Randle M. Gallucci Kelly M. Standifer Kelly M. Standifer |
| author_facet | Patrick Dib Yong Zhang Michael A. Ihnat Michael A. Ihnat Michael A. Ihnat Randle M. Gallucci Randle M. Gallucci Randle M. Gallucci Kelly M. Standifer Kelly M. Standifer |
| author_sort | Patrick Dib |
| collection | DOAJ |
| description | Post-Traumatic Stress Disorder (PTSD) is a debilitating mental health disorder that occurs after exposure to a traumatic event. Patients with comorbid chronic pain experience affective distress, worse quality of life, and poorer responses to treatments for pain or PTSD than those with either condition alone. FDA-approved PTSD treatments are often ineffective analgesics, requiring additional drugs to treat co-morbid symptoms. Therefore, development of new treatment strategies necessitate a better understanding of the pathophysiology of PTSD and comorbid pain. The single prolonged stress (SPS) model of PTSD induces the development of persistent mechanical allodynia and thermal hyperalgesia. Increased Nociceptin/Orphanin FQ (N/OFQ) levels in serum and CSF accompany these exaggerated nociceptive responses, as well as increased serum levels of the pro-inflammatory cytokine tumor necrosis factor (TNF-α). Therefore, the primary goal was to determine the role of TNF-α in the development of SPS-induced allodynia/hyperalgesia and elevated serum and CNS N/OFQ using two approaches: TNF-α synthesis inhibition, and blockade with anti-TNF-α antibody that acts primarily in the periphery. Administration of TNF-α synthesis blocker, thalidomide (THL), immediately after SPS prevented increased TNF-α and development of allodynia and hyperalgesia. The THL effect lasted at least 21 days, well after thalidomide treatment ended (day 5). THL also prevented SPS-induced increases in serum N/OFQ and reversed regional N/OFQ mRNA expression changes in the CNS. Serum TNF-α increases detected at 4 and 24 h post SPS were not accompanied by blood brain barrier disruption. A single injection of anti-TNF-α antibody to male and female rats during the SPS procedure prevented the development of allodynia, hyperalgesia, and elevated serum N/OFQ, and reduced SPS-induced anxiety-like behaviors in males. Anti-TNFα treatment also blocked development of SPS-induced allodynia in females, and blocked increased hypothalamic N/OFQ in males and females. This suggests that a peripheral TNF-α surge is necessary for the initiation of allodynia associated with SPS, as well as the altered central and peripheral N/OFQ that maintains nociceptive sensitivity. Therefore, early alleviation of TNF-α provides new therapeutic options for investigation as future PTSD and co-morbid pain treatments. |
| first_indexed | 2024-12-22T10:31:45Z |
| format | Article |
| id | doaj.art-acae682e04674aaebd6dc089b9464ed1 |
| institution | Directory Open Access Journal |
| issn | 1664-0640 |
| language | English |
| last_indexed | 2024-12-22T10:31:45Z |
| publishDate | 2021-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Psychiatry |
| spelling | doaj.art-acae682e04674aaebd6dc089b9464ed12022-12-21T18:29:19ZengFrontiers Media S.A.Frontiers in Psychiatry1664-06402021-08-011210.3389/fpsyt.2021.721999721999TNF-Alpha as an Initiator of Allodynia and Anxiety-Like Behaviors in a Preclinical Model of PTSD and Comorbid PainPatrick Dib0Yong Zhang1Michael A. Ihnat2Michael A. Ihnat3Michael A. Ihnat4Randle M. Gallucci5Randle M. Gallucci6Randle M. Gallucci7Kelly M. Standifer8Kelly M. Standifer9Department of Pharmaceutical Sciences, University of Oklahoma College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United StatesDepartment of Pharmaceutical Sciences, University of Oklahoma College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United StatesDepartment of Pharmaceutical Sciences, University of Oklahoma College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United StatesHarold Hamm Diabetes Center, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United StatesDepartment of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United StatesDepartment of Pharmaceutical Sciences, University of Oklahoma College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United StatesHarold Hamm Diabetes Center, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United StatesDepartment of Cell Biology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United StatesDepartment of Pharmaceutical Sciences, University of Oklahoma College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United StatesHarold Hamm Diabetes Center, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United StatesPost-Traumatic Stress Disorder (PTSD) is a debilitating mental health disorder that occurs after exposure to a traumatic event. Patients with comorbid chronic pain experience affective distress, worse quality of life, and poorer responses to treatments for pain or PTSD than those with either condition alone. FDA-approved PTSD treatments are often ineffective analgesics, requiring additional drugs to treat co-morbid symptoms. Therefore, development of new treatment strategies necessitate a better understanding of the pathophysiology of PTSD and comorbid pain. The single prolonged stress (SPS) model of PTSD induces the development of persistent mechanical allodynia and thermal hyperalgesia. Increased Nociceptin/Orphanin FQ (N/OFQ) levels in serum and CSF accompany these exaggerated nociceptive responses, as well as increased serum levels of the pro-inflammatory cytokine tumor necrosis factor (TNF-α). Therefore, the primary goal was to determine the role of TNF-α in the development of SPS-induced allodynia/hyperalgesia and elevated serum and CNS N/OFQ using two approaches: TNF-α synthesis inhibition, and blockade with anti-TNF-α antibody that acts primarily in the periphery. Administration of TNF-α synthesis blocker, thalidomide (THL), immediately after SPS prevented increased TNF-α and development of allodynia and hyperalgesia. The THL effect lasted at least 21 days, well after thalidomide treatment ended (day 5). THL also prevented SPS-induced increases in serum N/OFQ and reversed regional N/OFQ mRNA expression changes in the CNS. Serum TNF-α increases detected at 4 and 24 h post SPS were not accompanied by blood brain barrier disruption. A single injection of anti-TNF-α antibody to male and female rats during the SPS procedure prevented the development of allodynia, hyperalgesia, and elevated serum N/OFQ, and reduced SPS-induced anxiety-like behaviors in males. Anti-TNFα treatment also blocked development of SPS-induced allodynia in females, and blocked increased hypothalamic N/OFQ in males and females. This suggests that a peripheral TNF-α surge is necessary for the initiation of allodynia associated with SPS, as well as the altered central and peripheral N/OFQ that maintains nociceptive sensitivity. Therefore, early alleviation of TNF-α provides new therapeutic options for investigation as future PTSD and co-morbid pain treatments.https://www.frontiersin.org/articles/10.3389/fpsyt.2021.721999/fullhyperalgesiaallodynianociceptin/orphanin FQ (N/OFQ)traumatic stressthalidomideNOP receptor |
| spellingShingle | Patrick Dib Yong Zhang Michael A. Ihnat Michael A. Ihnat Michael A. Ihnat Randle M. Gallucci Randle M. Gallucci Randle M. Gallucci Kelly M. Standifer Kelly M. Standifer TNF-Alpha as an Initiator of Allodynia and Anxiety-Like Behaviors in a Preclinical Model of PTSD and Comorbid Pain Frontiers in Psychiatry hyperalgesia allodynia nociceptin/orphanin FQ (N/OFQ) traumatic stress thalidomide NOP receptor |
| title | TNF-Alpha as an Initiator of Allodynia and Anxiety-Like Behaviors in a Preclinical Model of PTSD and Comorbid Pain |
| title_full | TNF-Alpha as an Initiator of Allodynia and Anxiety-Like Behaviors in a Preclinical Model of PTSD and Comorbid Pain |
| title_fullStr | TNF-Alpha as an Initiator of Allodynia and Anxiety-Like Behaviors in a Preclinical Model of PTSD and Comorbid Pain |
| title_full_unstemmed | TNF-Alpha as an Initiator of Allodynia and Anxiety-Like Behaviors in a Preclinical Model of PTSD and Comorbid Pain |
| title_short | TNF-Alpha as an Initiator of Allodynia and Anxiety-Like Behaviors in a Preclinical Model of PTSD and Comorbid Pain |
| title_sort | tnf alpha as an initiator of allodynia and anxiety like behaviors in a preclinical model of ptsd and comorbid pain |
| topic | hyperalgesia allodynia nociceptin/orphanin FQ (N/OFQ) traumatic stress thalidomide NOP receptor |
| url | https://www.frontiersin.org/articles/10.3389/fpsyt.2021.721999/full |
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