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Article ; Online: Learning pain in context: Response-conditioned placebo analgesia and nocebo hyperalgesia in male rats with chronic neuropathic pain.

Boorman, Damien C / Keay, Kevin A

2023 Volume 263, Page(s) 114116

Abstract: Background: Animal models of placebo analgesia and nocebo hyperalgesia have great potential to assist in the development of novel treatments for chronic pain that exploit or inhibit these phenomena. This study sought to elicit both conditioned placebo ... ...

Abstract	Background: Animal models of placebo analgesia and nocebo hyperalgesia have great potential to assist in the development of novel treatments for chronic pain that exploit or inhibit these phenomena. This study sought to elicit both conditioned placebo analgesia and conditioned nocebo hyperalgesia in rats with chronic neuropathic pain using non-pharmacological, contextual conditioning approaches, similar to those most often used in humans. Methods: Sciatic nerve-injured male Sprague-Dawley rats (n = 80), and sham controls (n = 16), underwent a conditioning procedure in which three different thermal stimulus intensities (4 °C, 20 °C or 30 °C) were paired with contextual cues. Injured hind paw withdrawal behaviours were used to determine pain sensitivity, and either conditioned analgesia or conditioned hyperalgesia was evoked by re-exposing the rats to the same context with either an increased or decreased thermal stimulus, respectively. Results: Stronger conditioned analgesia and conditioned hyperalgesia were seen when rats were conditioned in a more complex environment, highlighting the importance of context in these processes. Rats that did not undergo conditioning procedures showed fewer hind paw withdrawals, indicating a learned component to these pain behaviours. Conclusions: Our data call attention to context and learning as two critical factors in the development of placebo and nocebo effects in male rodents with a neuropathic injury. Additionally, the response-conditioning model we present in this study affords better comparisons between human and animal studies, in particular for those seeking to identify commonalities in the neurobiological mechanisms of placebo and nocebo responses.
MeSH term(s)	Humans ; Rats ; Male ; Animals ; Hyperalgesia/drug therapy ; Nocebo Effect ; Rats, Sprague-Dawley ; Neuralgia ; Analgesia
Language	English
Publishing date	2023-02-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3907-x
ISSN	1873-507X ; 0031-9384
ISSN (online)	1873-507X
ISSN	0031-9384
DOI	10.1016/j.physbeh.2023.114116
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Zs.A 747: Show issues

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Article ; Online: Re-examining the Mysterious Role of the Cerebellum in Pain.

Li, Crystal N / Keay, Kevin A / Henderson, Luke A / Mychasiuk, Richelle

The Journal of neuroscience : the official journal of the Society for Neuroscience

2024 Volume 44, Issue 17

Abstract: Pain is considered a multidimensional experience that embodies not merely sensation, but also emotion and perception. As is appropriate for this complexity, pain is represented and processed by an extensive matrix of cortical and subcortical structures. ... ...

Abstract	Pain is considered a multidimensional experience that embodies not merely sensation, but also emotion and perception. As is appropriate for this complexity, pain is represented and processed by an extensive matrix of cortical and subcortical structures. Of these structures, the cerebellum is gaining increasing attention. Although association between the cerebellum and both acute and chronic pain have been extensively detailed in electrophysiological and neuroimaging studies, a deep understanding of what functions are mediated by these associations is lacking. Nevertheless, the available evidence implies that lobules IV-VI and Crus I are especially pertinent to pain processing, and anatomical studies reveal that these regions connect with higher-order structures of sensorimotor, emotional, and cognitive function. Therefore, we speculate that the cerebellum exerts a modulatory role in pain via its communication with sites of sensorimotor, executive, reward, and limbic function. On this basis, in this review, we propose numerous ways in which the cerebellum might contribute to both acute and chronic pain, drawing particular attention to emotional and cognitive elements of pain. In addition, we emphasise the importance of advancing our knowledge about the relationship between the cerebellum and pain by discussing novel therapeutic opportunities that capitalize on this association.
MeSH term(s)	Humans ; Cerebellum/physiopathology ; Cerebellum/diagnostic imaging ; Animals ; Pain/physiopathology ; Pain/psychology ; Emotions/physiology
Language	English
Publishing date	2024-04-24
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.1538-23.2024
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Article ; Online: Sex differences in morphine sensitivity are associated with differential glial expression in the brainstem of rats with neuropathic pain.

Boorman, Damien C / Keay, Kevin A

Journal of neuroscience research

2022 Volume 100, Issue 10, Page(s) 1890–1907

Abstract: Chronic pain is more prevalent and reported to be more severe in women. Opioid analgesics are less effective in women and result in stronger nauseant effects. The neurobiological mechanisms underlying these sex differences have yet to be clearly defined, ...

Abstract	Chronic pain is more prevalent and reported to be more severe in women. Opioid analgesics are less effective in women and result in stronger nauseant effects. The neurobiological mechanisms underlying these sex differences have yet to be clearly defined, though recent research has suggested neuronal-glial interactions are likely involved. We have previously shown that similar to people, morphine is less effective at reducing pain behaviors in female rats. In this study, we used the immunohistochemical detection of glial fibrillary acidic protein (GFAP) expression to investigate sex differences in astrocyte density and morphology in six medullary regions known to be modulated by pain and/or opioids. Morphine administration had small sex-dependent effects on overall GFAP expression, but not on astrocyte morphology, in the rostral ventromedial medulla, the subnucleus reticularis dorsalis, and the area postrema. Significant sex differences in the density and morphology of GFAP immunopositive astrocytes were detected in all six regions. In general, GFAP-positive cells in females showed smaller volumes and reduced complexity than those observed in males. Furthermore, females showed lower overall GFAP expression in all regions except for the area postrema, the critical medullary region responsible for opioid-induced nausea and emesis. These data support the possibility that differences in astrocyte activity might underlie the sex differences seen in the processing of opioids in the context of chronic neuropathic pain.
MeSH term(s)	Analgesics, Opioid/pharmacology ; Animals ; Astrocytes/metabolism ; Brain Stem ; Female ; Glial Fibrillary Acidic Protein/metabolism ; Humans ; Male ; Morphine/pharmacology ; Neuralgia/metabolism ; Neuroglia/metabolism ; Rats ; Sex Characteristics
Chemical Substances	Analgesics, Opioid ; Glial Fibrillary Acidic Protein ; Morphine (76I7G6D29C)
Language	English
Publishing date	2022-07-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	195324-2
ISSN	1097-4547 ; 0360-4012
ISSN (online)	1097-4547
ISSN	0360-4012
DOI	10.1002/jnr.25103
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Zs.A 1232: Show issues

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Article ; Online: The impact of sciatic nerve injury and social interactions testing on glucocorticoid receptor expression in catecholaminergic medullary cell populations.

Sosa, Maria K S / Boorman, Damien C / Keay, Kevin A

Brain research

2023 Volume 1819, Page(s) 148542

Abstract: Paradoxically, while acute pain leads to transiently elevated corticosterone, chronic pain does not result in persistently elevated corticosterone. In the sciatic nerve chronic constriction injury (CCI) model of chronic pain, we have shown that the same ... ...

Abstract	Paradoxically, while acute pain leads to transiently elevated corticosterone, chronic pain does not result in persistently elevated corticosterone. In the sciatic nerve chronic constriction injury (CCI) model of chronic pain, we have shown that the same nerve injury produces a range of behavioural outcomes, each associated with distinctive adaptations to the HPA-axis to achieve stable plasma corticosterone levels. We also demonstrated that CRF and GR expression in the paraventricular hypothalamus (PVH) was increased in rats that showed persistent changes to their social behaviours during Resident-Intruder testing ('Persistent Effect' rats) when compared to rats that showed no behavioural changes ('No Effect' rats). In this study, we investigated whether these changes were driven in part by altered sensitivity of the brainstem catecholaminergic pathways (known to regulate the PVH) to glucocorticoids. GR expression in adrenergic (C1,C2) and noradrenergic (A1,A2) cells was determined using immunohistochemistry in behaviourally tested CCI rats and in uninjured controls. We found no differences between Persistent Effect and No Effect rats in (1) the glucocorticoid sensitivity of these cells, or (2) the numbers of adrenergic and noradrenergic cells in each region. However, we discovered an overall reduction in GR expression in the non-catecholaminergic cells of these regions in both experimental groups when compared to uninjured controls, most likely attributable to the repeated Resident-Intruder testing. Taken together, these data suggest strongly that brainstem mechanisms are unlikely to play a key role in the rebalancing of the HPA-axis triggered by CCI, increasing the probability that these changes are driven by supra-hypothalamic regions.
MeSH term(s)	Rats ; Animals ; Glucocorticoids/metabolism ; Receptors, Glucocorticoid/metabolism ; Rats, Sprague-Dawley ; Corticosterone ; Social Interaction ; Chronic Pain ; Behavior, Animal/physiology ; Sciatic Neuropathy/metabolism ; Peripheral Nerve Injuries ; Sciatic Nerve/injuries ; Adrenergic Agents
Chemical Substances	Glucocorticoids ; Receptors, Glucocorticoid ; Corticosterone (W980KJ009P) ; Adrenergic Agents
Language	English
Publishing date	2023-08-19
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/j.brainres.2023.148542
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Zs.A 161: Show issues

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Article ; Online: Escalating morphine dosage fails to elicit conditioned analgesia in a preclinical chronic neuropathic pain model.

Boorman, Damien C / Keay, Kevin A

Behavioural pharmacology

2021 Volume 32, Issue 6, Page(s) 479–486

Abstract: Many people with chronic pain escalate their opioid dosage to counteract tolerance effects. A treatment regimen consisting of placebos admixed with opioids has been suggested as a possible therapeutic option that could reduce the harm of long-term opioid ...

Abstract	Many people with chronic pain escalate their opioid dosage to counteract tolerance effects. A treatment regimen consisting of placebos admixed with opioids has been suggested as a possible therapeutic option that could reduce the harm of long-term opioid use. However, the analgesic efficacy of such a regimen requires further investigation before widespread adoption. We have recently reported that a 4-day pharmacological conditioning procedure, which paired morphine (6 mg/kg) with contextual cues, elicited placebo analgesia in subpopulations of male (35%) and female (25%) rats with sciatic nerve chronic constriction injury (CCI). Here, we investigated how an escalating morphine dosage during conditioning affects the incidence and strength of placebo analgesia. Forty-four male, Sprague-Dawley rats received CCI. Thirty-eight (86%) rats developed strong cold allodynia by day 6 post-surgery, as measured by hind paw withdrawal (HPW) behaviour on a 5°C cold plate (120 s). In this experiment, pharmacological conditioning consisted of an escalating morphine dose over 4 days (8/9/10/12 mg/kg). This dosing regimen produced strong reductions in HPW behaviour and counteracted the effects of morphine tolerance during conditioning. However, none of the rats given the placebo treatment (n = 12) demonstrated reductions in HPW behaviour when morphine was substituted for saline (i.e. placebo analgesia), but instead showed a strong behavioural response (rearing). These results demonstrate that a high, escalating dose of morphine failed to produce conditioned placebo analgesia in rats with CCI. It is possible that admixing placebos with opioids may be similarly ineffective in chronic pain patients when the opioids regimen is high or escalating.
MeSH term(s)	Animals ; Rats ; Analgesics, Opioid/pharmacology ; Behavior, Animal/drug effects ; Chronic Pain/drug therapy ; Chronic Pain/psychology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Dosage Calculations ; Drug Tolerance ; Long Term Adverse Effects/chemically induced ; Long Term Adverse Effects/prevention & control ; Morphine/pharmacology ; Neuralgia/drug therapy ; Neuralgia/psychology ; Placebo Effect ; Rats, Sprague-Dawley
Chemical Substances	Analgesics, Opioid ; Morphine (76I7G6D29C)
Language	English
Publishing date	2021-07-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1027374-8
ISSN	1473-5849 ; 0955-8810
ISSN (online)	1473-5849
ISSN	0955-8810
DOI	10.1097/FBP.0000000000000642
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Zs.A 2883: Show issues

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Article ; Online: Altruism in death: Attitudes to body and organ donation in Australian students.

Jenkin, Rebekah A / Garrett, Samuel A / Keay, Kevin A

Anatomical sciences education

2022 Volume 16, Issue 1, Page(s) 27–46

Abstract: Health education, research, and training rely on the altruistic act of body donation for the supply of cadavers. Organ transplantation and research rely on donated organs. Supply of both is limited, with further restrictions in Australia due to ... ...

Abstract	Health education, research, and training rely on the altruistic act of body donation for the supply of cadavers. Organ transplantation and research rely on donated organs. Supply of both is limited, with further restrictions in Australia due to requirements for a next-of-kin agreement to donation, irrespective of the deceased's pre-death consent. Research suggests health workers are less likely to support the donation of their own bodies and/or organs, despite recognizing the public good of donation, and that exposure to gross anatomy teaching may negatively affect support for donation. Attitudes to body and organ donation were examined in Australian students studying anatomy. Support for self-body donation (26.5%) was much lower than support for self-organ donation (82.5%). Ten percent of participants would not support the election of a family member or member of the public to donate their body, and just over 4% would not support the election of a family member to donate their organs, with one-to-two percent not supporting this election by a member of the public. Exposure to gross anatomy teaching was associated with an increased likelihood of consideration of issues about body and organ donation, whether for self, family, or the public, and registration as an organ donor. Exposure decreased participants' willingness to donate their own body, with those who practiced a religion least likely to support body donation. Gross anatomy courses provide an opportunity to inform future healthcare workers about altruistic donation, albeit with a recognition that religious or cultural beliefs may affect willingness to donate.
MeSH term(s)	Humans ; Altruism ; Anatomy/education ; Australia ; Surveys and Questionnaires ; Tissue and Organ Procurement ; Students ; Tissue Donors ; Health Knowledge, Attitudes, Practice
Language	English
Publishing date	2022-04-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2483491-9
ISSN	1935-9780 ; 1935-9772
ISSN (online)	1935-9780
ISSN	1935-9772
DOI	10.1002/ase.2180
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Zs.A 6787: Show issues

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Article ; Online: Sciatic nerve injury rebalances the hypothalamic-pituitary-adrenal axis in rats with persistent changes to their social behaviours.

Sosa, M Karmina / Boorman, Damien C / Keay, Kevin A

Journal of neuroendocrinology

2022 Volume 34, Issue 6, Page(s) e13131

Abstract: Increased glucocorticoids characterise acute pain responses, but not the chronic pain state, suggesting specific modifications to the hypothalamic-pituitary-adrenal (HPA)-axis preventing the persistent nature of chronic pain from elevating basal ... ...

Abstract	Increased glucocorticoids characterise acute pain responses, but not the chronic pain state, suggesting specific modifications to the hypothalamic-pituitary-adrenal (HPA)-axis preventing the persistent nature of chronic pain from elevating basal glucocorticoid levels. Individuals with chronic pain mount normal HPA-axis responses to acute stressors, indicating a rebalancing of the circuits underpinning these responses. Preclinical models of chronic neuropathic pain generally recapitulate these clinical observations, but few studies have considered that the underlying neuroendocrine circuitry may be altered. Additionally, individual differences in the behavioural outcomes of these pain models, which are strikingly similar to the range of behavioural subpopulations that manifest in response to stress, threat and motivational cues, may also be reflected in divergent patterns of HPA-axis activity, which characterises these other behavioural subpopulations. We investigated the effects of sciatic nerve chronic constriction injury (CCI) on adrenocortical and hypothalamic markers of HPA-axis activity in the subpopulation of rats showing persistent changes in social interactions after CCI (Persistent Effect) and compared them with rats that do not show these changes (No Effect). Basal plasma corticosterone did not change after CCI and did not differ between groups. However, adrenocortical sensitivity to adrenocorticotropic hormone (ACTH) diverged between these groups. No Effect rats showed large increases in basal plasma ACTH with no change in adrenocortical melanocortin 2 receptor (MC
MeSH term(s)	Adrenocorticotropic Hormone/metabolism ; Animals ; Chronic Pain/metabolism ; Corticosterone ; Corticotropin-Releasing Hormone/metabolism ; Glucocorticoids/metabolism ; Hypothalamo-Hypophyseal System ; Pituitary-Adrenal System ; Rats ; Receptors, Glucocorticoid/metabolism ; Sciatic Nerve/metabolism ; Social Behavior
Chemical Substances	Glucocorticoids ; Receptors, Glucocorticoid ; Adrenocorticotropic Hormone (9002-60-2) ; Corticotropin-Releasing Hormone (9015-71-8) ; Corticosterone (W980KJ009P)
Language	English
Publishing date	2022-04-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1007517-3
ISSN	1365-2826 ; 0953-8194
ISSN (online)	1365-2826
ISSN	0953-8194
DOI	10.1111/jne.13131
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Zs.A 2634: Show issues

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Article ; Online: Morphine-Conditioned Placebo Analgesia in Female and Male Rats with Chronic Neuropathic Pain: c-Fos Expression in the Rostral Ventromedial Medulla.

Boorman, Damien C / Keay, Kevin A

Neuroscience

2020 Volume 457, Page(s) 51–73

Abstract: Placebo analgesia has great potential to overcome the inadequacies of current drug therapies to treat conditions of chronic pain. The rostral ventromedial medulla (RVM) has been implicated as a critical relay in the antinociceptive pathway underpinning ... ...

Abstract	Placebo analgesia has great potential to overcome the inadequacies of current drug therapies to treat conditions of chronic pain. The rostral ventromedial medulla (RVM) has been implicated as a critical relay in the antinociceptive pathway underpinning placebo analgesia in humans. We developed a model of opiate-conditioned placebo analgesia in rats with neuropathic injury to identify medullary nuclei active during placebo analgesia. Using female and male rats the degree of thermal allodynia was first determined following nerve injury, and a pharmacological conditioning procedure, pairing contextual cues with the experience of morphine-induced analgesia, was used to elicit placebo analgesic reactions. This protocol revealed clear subpopulations of placebo reactors (36% of males, 25% of females) and non-reactors in proportions similar to those reported in human studies. We detected injury-specific c-Fos expression in the gracile nucleus and morphine-specific c-Fos expression in the serotonergic midline raphe nuclei and the caudal nuclei of the solitary tract. However, c-Fos expression did not differ between placebo reactors and non-reactors in either serotonergic or non-serotonergic neurons of the RVM. Despite a subpopulation of rats demonstrating placebo reactions, we found no evidence for enhanced activity in the nuclei from which the classical RVM → spinal cord descending analgesic pathways emerge.
MeSH term(s)	Analgesia ; Animals ; Female ; Male ; Medulla Oblongata ; Morphine/pharmacology ; Neuralgia/drug therapy ; Rats ; Rats, Sprague-Dawley
Chemical Substances	Morphine (76I7G6D29C)
Language	English
Publishing date	2020-12-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	196739-3
ISSN	1873-7544 ; 0306-4522
ISSN (online)	1873-7544
ISSN	0306-4522
DOI	10.1016/j.neuroscience.2020.11.038
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Article ; Online: Corrigendum: Brainstem Pain-Modulation Circuitry and Its Plasticity in Neuropathic Pain: Insights From Human Brain Imaging Investigations.

Mills, Emily P / Keay, Kevin A / Henderson, Luke A

Frontiers in pain research (Lausanne, Switzerland)

2021 Volume 2, Page(s) 812209

Abstract: This corrects the article DOI: 10.3389/fpain.2021.705345.]. ...

Abstract	[This corrects the article DOI: 10.3389/fpain.2021.705345.].
Language	English
Publishing date	2021-12-21
Publishing country	Switzerland
Document type	Published Erratum
ISSN	2673-561X
ISSN (online)	2673-561X
DOI	10.3389/fpain.2021.812209
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Article ; Online: Learning Pain in Context: Response-Conditioned Placebo Analgesia and Nocebo Hyperalgesia in Male Rats with Chronic Neuropathic Pain

Boorman, Damien C. / Keay, Kevin A.

Physiology & Behavior. 2023, p.114116-

2023 , Page(s) 114116–

Abstract: Animal models of placebo analgesia and nocebo hyperalgesia have great potential to assist in the development of novel treatments for chronic pain that exploit or inhibit these phenomena. This study sought to elicit both conditioned placebo analgesia and ... ...

Abstract	Animal models of placebo analgesia and nocebo hyperalgesia have great potential to assist in the development of novel treatments for chronic pain that exploit or inhibit these phenomena. This study sought to elicit both conditioned placebo analgesia and conditioned nocebo hyperalgesia in rats with chronic neuropathic pain using non-pharmacological, contextual conditioning approaches, similar to those used in humans. Sciatic nerve-injured male Sprague-Dawley rats (n=80), and sham controls (n=16) underwent a conditioning procedure in which three different thermal stimulus intensities (4°C, 20°C or 30°C) were paired with contextual cues. Injured hind paw withdrawal behaviours were used to determine pain sensitivity, and either conditioned analgesia or conditioned hyperalgesia was evoked by re-exposing the rats to the same context with either an increased or decreased thermal stimulus, respectively. Stronger conditioned analgesia and conditioned hyperalgesia were seen when rats were conditioned in a more complex environment, highlighting the importance of context in these processes. Rats that did not undergo conditioning procedures showed fewer hind paw withdrawals, indicating a learned component to these pain behaviours. Our data call attention to context and learning as two critical factors in the development of placebo and nocebo effects in male rodents with a neuropathic injury. Additionally, the response-conditioning model we present in this study affords better comparisons between human and animal studies, in particular for those seeking to identify commonalities in the neurobiological mechanisms of placebo and nocebo responses.
Keywords	analgesia ; behavior ; humans ; males ; models ; pain ; placebos ; somatosensory disorders ; Allodynia ; thermal sensitivity ; preclinical ; associative learning
Language	English
Publishing place	Elsevier Inc.
Document type	Article ; Online
Note	Pre-press version
ZDB-ID	3907-x
ISSN	1873-507X ; 0031-9384
ISSN (online)	1873-507X
ISSN	0031-9384
DOI	10.1016/j.physbeh.2023.114116
Database	NAL-Catalogue (AGRICOLA)

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