Pharmacology & Therapeutics (Scholarly Articles)

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  • Publication
    Hyporesponsivity to mu-opioid receptor agonism in the Wistar-Kyoto rat model of altered nociceptive responding associated with negative affective state.
    (Lippincott, Williams & Wilkins, 2020-08-17) Ferdousi, Mehnaz I.; Calcagno, Patricia; Clarke, Morgane; Aggarwal, Sonali; Sanchez, Connie; Smith, Karen L.; Eyerman, David J.; Kelly, John P.; Roche, Michelle; Finn, David P.; Science Foundation Ireland
    Chronic pain is often comorbid with anxiety and depression, altering the level of perceived pain, which negatively affects therapeutic outcomes. The role of the endogenous mu-opioid receptor (MOP) system in pain-negative affect interactions and the influence of genetic background thereon is poorly understood. The inbred Wistar-Kyoto (WKY) rat, which mimics aspects of anxiety and depression, displays increased sensitivity (hyperalgesia) to noxious stimuli, compared to Sprague-Dawley (SD) rats. Here, we report that WKY rats are hyporesponsive to the antinociceptive effects of systemically administered MOP agonist morphine in the hot plate and formalin tests, compared to SD counterparts. Equivalent plasma morphine levels in the two rat strains suggested that these differences in morphine sensitivity were unlikely to be due to strain-related differences in morphine pharmacokinetics. Although MOP expression in the ventrolateral periaqueductal grey (vlPAG) did not differ between WKY and SD rats, the vlPAG was identified as a key locus for the hyporesponsivity to MOP agonism in WKY rats in the formalin test. Moreover, morphine-induced effects on c-Fos (a marker of neuronal activity) in regions downstream of vlPAG, namely the rostral ventromedial medulla and lumbar spinal dorsal horn, were blunted in the WKY rats. Together, these findings suggest that a deficit in MOP-induced recruitment of the descending inhibitory pain pathway may underlie hyperalgesia to noxious inflammatory pain in the WKY rat strain genetically predisposed to negative affect.
  • Publication
    Pharmacological blockade of PPAR isoforms increases conditioned fear responding in the presence of nociceptive tone
    (MDPI, 2020-02-24) Gaspar, Jessica C.; Okine, Bright N.; Llorente-Berzal, Alvaro; Roche, Michelle; Finn, David P.; Conselho Nacional de Pesquisa (CNPq) Brazil; Science Foundation Ireland; Irish Research Council
    Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors with three isoforms (PPAR¿, PPARß/¿, PPAR¿) and can regulate pain, anxiety, and cognition. However, their role in conditioned fear and pain-fear interactions has not yet been investigated. Here, we investigated the effects of systemically administered PPAR antagonists on formalin-evoked nociceptive behaviour, fear-conditioned analgesia (FCA), and conditioned fear in the presence of nociceptive tone in rats. Twenty-three and a half hours following fear conditioning to context, male Sprague-Dawley rats received an intraplantar injection of formalin and intraperitoneal administration of vehicle, PPAR¿ (GW6471), PPARß/¿ (GSK0660) or PPAR¿ (GW9662) antagonists, and 30 min later were re-exposed to the conditioning arena for 15 min. The PPAR antagonists did not alter nociceptive behaviour or fear-conditioned analgesia. The PPAR¿ and PPARß/¿ antagonists prolonged context-induced freezing in the presence of nociceptive tone without affecting its initial expression. The PPAR¿ antagonist potentiated freezing over the entire trial. In conclusion, pharmacological blockade of PPAR¿ and PPARß/¿ in the presence of formalin-evoked nociceptive tone, impaired short-term, within-trial fear-extinction in rats without affecting pain response, while blockade of PPAR¿ potentiated conditioned fear responding. These results suggest that endogenous signalling through these three PPAR isoforms may reduce the expression of conditioned fear in the presence of nociceptive tone.
  • Publication
    PPARs and pain
    (Wiley, 2018-04-21) Okine, Bright N.; Gaspar, Jessica C.; Finn, David P.; Science Foundation Ireland; Irish Research Council; Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil; National University of Ireland, Galway
    Chronic pain is a common cause of disability worldwide and remains a global health and socio-economic challenge. Current analgesics are either ineffective in a significant proportion of patients with chronic pain or associated with significant adverse side effects. The PPARs, a family of nuclear hormone transcription factors, have emerged as important modulators of pain in preclinical studies and therefore a potential therapeutic target for the treatment of pain. Modulation of nociceptive processing by PPARs is likely to involve both transcription-dependent and transcription-independent mechanisms. This review presents a comprehensive overview of preclinical studies investigating the contribution of PPAR signalling to nociceptive processing in animal models of inflammatory and neuropathic pain. We examine current evidence from anatomical, molecular and pharmacological studies demonstrating a role for PPARs in pain control. We also discuss the limited evidence available from relevant clinical studies and identify areas that warrant further research.
  • Publication
    Differential role of anterior cingulate cortical glutamatergic neurons in pain-related aversion learning and nociceptive behaviors in male and female rats
    (Frontiers Media, 2020-08-11) Jarrin, Sarah; Pandit, Abhay; Roche, Michelle; Finn, David P.; Science Foundation Ireland; European Regional Development Fund
    Pain is comprised of both sensory and affective components. The anterior cingulate cortex (ACC) is a key brain region involved in the emotional processing of pain. Specifically, glutamatergic transmission within the ACC has been shown to modulate pain-related aversion. In the present study, we usein vivooptogenetics to activate or silence, using channelrhodopsin (ChR2) and archaerhodopsin (ArchT) respectively, calmodulin-kinase II alpha (CaMKII alpha)-expressing excitatory glutamatergic neurons of the ACC during a formalin-induced conditioned place aversion (F-CPA) behavioral paradigm in both female and male adult Sprague-Dawley rats. Expression of c-Fos, a marker of neuronal activity, was assessed within the ACC using immunohistochemistry. Optogenetic inhibition of glutamatergic neurons of the ACC abolished F-CPA without affecting formalin-induced nociceptive behavior during conditioning. In male rats, optogenetic activation of ACC glutamatergic neurons decreased formalin-induced nociceptive behavior during conditioning without affecting F-CPA. Interestingly, the opposite effect was seen in females, where optogenetic activation of glutamatergic neurons of the ACC increased formalin-induced nociceptive behavior during conditioning. The abolition of F-CPA following optogenetic inhibition of glutamatergic neurons of the ACC was associated with a reduction in c-Fos immunoreactivity in the ACC in male rats, but not female rats. These results suggest that excitatory glutamatergic neurons of the ACC play differential and sex-dependent roles in the aversion learning and acute sensory components of pain.
  • Publication
    Antinociceptive effects of the GPR55 Antagonist CID16020046 injected into the rat anterior cingulate cortex
    (Elsevier, 2020-07-13) Okine, Bright N.; Mc Laughlin, Gemma; Gaspar, Jessica C.; Harhen, Brendan; Roche, Michelle; Finn, David P.; Science Foundation Ireland; Conselho Nacionalde Desenvolvimento Cientifico e Tecnologico, Brazil
    The G-protein coupled receptor, GPR55, modulates nociceptive processing. Given the expression of GPR55 in the anterior cingulate cortex (ACC), a key brain region involved in the cognitive and affective dimensions of pain, the present study tested the hypothesis that GPR55 signalling in the ACC facilitates inflammatory pain behaviour in rats. The expression of GPR55 in the ACC was confirmed by both western blotting and immunostaining, with evidence for neuronal localisation. Microinjection of the selective GPR55 antagonist CID16020046 into the ACC of adult male Sprague-Dawley rats significantly reduced second phase formalin-evoked nociceptive behaviour compared with vehicle-treated controls. CID16020046 administration was associated with a reduction in phosphorylation of extracellular signal-regulated kinase (ERK), a downstream target of GPR55 activation, in the ACC. Intra-ACC administration of CID16020046 prevented the formalin-induced increases in expression of mRNA coding for the immediate early gene and marker of neuronal activity, c-Fos, in the ipsilateral dorsal horn of the spinal cord. Intra-plantar injection of formalin reduced tissue levels of the endogenous GPR55 ligand 2-arachidonoyl-sn-glycero-3-phosphoinositol (2-AGPI) in the ACC, likely reflecting its increased release/utilisation. These data suggest that endogenous activation of GPR55 signalling and increased ERK phosphorylation in the ACC facilitates inflammatory pain via top-down modulation of descending pain control. (C) 2020 IBRO. Published by Elsevier Ltd. All rights reserved.
  • Publication
    Attenuation of fear‐conditioned analgesia in rats by monoacylglycerol lipase inhibition in the anterior cingulate cortex: Potential role for CB2 receptors
    (The British Pharmacological Society, 2020-01-22) Corcoran, Louise; Mattimoe, Darragh; Roche, Michelle; Finn, David P.; Science Foundation Ireland
    Improved understanding of brain mechanisms regulating endogenous analgesia is important from a fundamental physiological perspective and for identification of novel therapeutic strategies for pain. The endocannabinoid system plays a key role in stress-induced analgesia, including fear-conditioned analgesia (FCA), a potent form of endogenous analgesia. Here we studied the role of the endocannabinoid 2-arachidonoyl glycerol (2-AG) within the anterior cingulate cortex (ACC; a brain region implicated in the affective component of pain) in FCA in rats. FCA was modelled in male Lister-hooded rats by assessing formalin-evoked nociceptive behaviour in an arena previously paired with footshock. The effects of intra-ACC administration of MJN110 (inhibitor of monoacylglycerol lipase [MGL], the primary enzyme catabolising 2-AG), AM630 (CB2 receptor antagonist), AM251 (CB1 receptor antagonist), or MJN110+AM630 on FCA were assessed. MJN110 attenuated FCA when microinjected into the ACC, an effect associated with increased levels of 2-AG in the ACC. This effect of MJN110 on FCA was unaltered by co-administration of AM251 but was blocked by AM630, which alone reduced nociceptive behaviour in non-fear-conditioned rats. RT-qPCR confirmed that mRNA encoding CB1 and CB2 receptors was detectable in the ACC of formalin-injected rats, and unchanged in those expressing FCA. These results suggest that a MGL substrate in the ACC, likely 2-AG, modulates FCA, and that within the ACC, 2-AG-CB2 receptor signalling may suppress this form of endogenous analgesia. These results may facilitate increased understanding and improved treatment of, pain- and fear-related disorders and their comorbidity.
  • Publication
    Effects of direct periaqueductal grey administration of a cannabinoid receptor agonist on nociceptive and aversive responses in rats
    (Elsevier, 2003-07-31) Finn, David P.; Jhaveri, M.D.; Jhaveri, Maulik D.; Beckett, Simon Richard Graham; Roe, Clare H.; Kendall, David A.; Marsden, Charles Alexander; Chapman, Victoria; Wellcome Trust
    The analgesic potential of cannabinoids may be hampered by their ability to produce aversive emotion when administered systemically. We investigated the hypothesis that the midbrain periaqueductal grey (PAG) is a common substrate mediating the anti-nociceptive and potential aversive effects of cannabinoids. The rat formalin test was used to model nociceptive behaviour. Intra-PAG microinjection of the excitatory amino acid d,l-homocysteic acid (DLH) was used to induce an aversive, panic-like reaction characteristic of the defensive “fight or flight” response. Administration of the cannabinoid receptor agonist HU210 (5 μg/rat) into the dorsal PAG significantly reduced the second phase of formalin-evoked nociceptive behaviour, an effect which was blocked by co-administration of the CB1 receptor antagonist SR141716A (50 μg/rat). This anti-nociceptive effect was accompanied by an HU210-induced attenuation of the formalin-evoked increase in Fos protein expression in the caudal lateral PAG. Intra-dorsal PAG administration of HU210 (0.1, 1 or 5 μg/rat) significantly reduced the aversive DLH-induced explosive locomotor response. The anti-nociceptive effect of HU210 is likely to result from activation of the descending inhibitory pain pathway. Mechanisms mediating the anti-aversive effects of cannabinoids in the PAG remain to be elucidated. These data implicate a role for the PAG in both cannabinoid-mediated anti-nociceptive and anti-aversive responses.
  • Publication
    Endocannabinoid-mediated enhancement of fear-conditioned analgesia in rats: Opioid receptor dependency and molecular correlates
    (International Association for the Study of Pain, 2008-12) Butler, Ryan K.; Rea, Kieran; Lang, Yvonne; Gavin, Aisling M.; Finn, David P.; Science Foundation Ireland
    The opioid and endocannabinoid systems mediate analgesia expressed upon re-exposure to a contextually aversive stimulus (fear-conditioned analgesia; FCA), and modulate the mitogen-activated protein kinase (MAPK) pathway. However, ail interaction between the opioid and endocannabinoid systems during FCA has not been investigated at the behavioural or molecular level. FCA was modeled in male Lister-hooded rats by assessing formalin-evoked nociceptive behaviour in ail arena previously paired with footshock. Administration of the fatty acid amide hydrolase and endocannabinoid catabolism inhibitor, URB597 (0.3 mg/kg, i.p.), enhanced expression of FCA. The opioid receptor antagonist, naloxone, attenuated FCA and attenuated the URB597-induced enhancement of FCA. SR141716A (CB, antagonist) and SR 144528 (CB2 antagonist) also attenuated the URB597-mediated enhancement of FCA. Expression of FCA was associated with increased relative phospho-ERK2 expression in the amygdala, ail effect blocked by naloxone, SR141716A, and SR144528. Furthermore, URB597-mediated enhancement of FCA was associated with reduced phospho-ER K I and phosplio-ERK2 in the amygdala. Phospho-ERK1/2 expression in the hippocampus, prefrontal cortex, and thalamus Was unchanged following FCA and drug treatment. None of the drugs affected formalin-evoked nociceptive behaviour or phospho-ERK1/2 expression in non-fear-conditioned rats. These data suggest that endocannabinoid-mediated enhancement of FCA is abolished by pharmacological blockade of opioid receptors as well as CB, or CB, receptors. Both pharmacological enhancement (with URB597) and attenuation (with naloxone) of this form of endogenous analgesia were associated with reduced expression of phospho-ERK1/2 in the amygdaloid complex arguing against a causal role for ERK1/2 signaling in the amygdala during expression of FCA or its modulation by opioids or cannabinoids. (C) 2008 International Association For the Study of Pain. Published by Elsevier B.V. All rights reserved.
  • Publication
    Impaired endocannabinoid signalling in the rostral ventromedial medulla underpins genotype-dependent hyper-responsivity to noxious stimuli
    (International Association for the Study of Pain, 2014-01) Rea, Kieran; Olango, Weredeselam M.; Okine, Bright N.; Madasu, Manish K.; McGuire, Iseult C.; Coyle, Kathleen; Harhen, Brendan; Roche, Michelle; Finn, David P.; Science Foundation Ireland
    Pain is both a sensory and an emotional experience, and is subject to modulation by a number of factors including genetic background modulating stress/affect. The Wistar-Kyoto (WKY) rat exhibits a stress-hyper-responsive and depressive-like phenotype and increased sensitivity to noxious stimuli, compared with other rat strains. Here, we show that this genotype-dependent hyperalgesia is associated with impaired pain-related mobilisation of endocannabinoids and transcription of their synthesising enzymes in the rostral ventromedial medulla (RVM). Pharmacological blockade of the Cannabinoid(1) (CB1) receptor potentiates the hyperalgesia in WKY rats, whereas inhibition of the endocannabinoid catabolising enzyme, fatty acid amide hydrolase, attenuates the hyperalgesia. The latter effect is mediated by CB1 receptors in the RVM. Together, these behavioural, neurochemical, and molecular data indicate that impaired endocannabinoid signalling in the RVM underpins hyper-responsivity to noxious stimuli in a genetic background prone to heightened stress/affect. (C) 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
  • Publication
    Evidence for differential modulation of conditioned aversion and fear‐conditioned analgesia by CB1 receptors
    (Wiley, 2004-07-15) Finn, David P.; Beckett, S. R. G.; Richardson, D.; Kendall, D. A.; Marsden, C. A.; Chapman, V.
    Fear‐conditioned analgesia is an important survival response mediated by substrates controlling nociception and aversion. Cannabinoid1 (CB1) receptors play an important role in nociception and aversion. However, their role in fear‐conditioned analgesia has not been investigated. This study investigated the effects of systemic administration of the CB1 receptor antagonist, SR141716A (1 mg/kg, ip), on fear‐conditioned analgesia and conditioned aversion in rats. Twenty‐four hours after receiving footshock, rats exhibited reduced formalin‐evoked nociceptive behaviour, increased freezing and increased defecation when tested in the footshock apparatus, compared with non‐footshocked formalin‐injected rats. SR141716A attenuated fear‐conditioned analgesia, freezing and defecation. Importantly, SR141716A had no effect on formalin‐evoked nociceptive behaviour over an equivalent time period in rats not receiving footshock. SR141716A had no effect on contextually induced freezing during the first half of the test trial in rats receiving intra‐plantar injection of saline. Administration of SR1417176A did, however, attenuate short‐term extinction of contextually induced freezing and ultrasound emission in rats receiving intra‐plantar saline, compared with vehicle‐treated saline controls. These data suggest an important role for the CB1 receptor in mediating fear‐conditioned analgesia and provide evidence for differential modulation of conditioned aversive behaviour by CB1 receptors during tonic, persistent pain.
  • Publication
    Development and characterization of a novel, anatomically relevant rat model of acute postoperative pain
    (Elsevier, 2015-01-30) Bree, Dara; Moriarty, Orla; O’Mahony, Cliona M.; Morris, Bradley; Bannerton, Karen; Broom, Daniel C.; Kelly, John P.; Roche, Michelle; Finn, David P.
    Acute postoperative pain remains a significant health care issue. Development of anatomically relevant animal models of postoperative pain, with improved predictive validity, would advance understanding of postoperative pain mechanisms and improve treatment outcomes. This study aimed to develop, characterize, and validate a rat model of acute postoperative pain associated with inguinal hernia repair based on the Lichtenstein inguinal hernia repair procedure (without hernia induction). We hypothesized that the surgery would result in reduced spontaneous locomotor activity, which would represent a pain-related phenotype. Postsurgical characterization involved extensive monitoring of home cage and open field locomotor activity, as well as mechanical hypersensitivity and assessment of c-Fos expression in the dorsal horn of the spinal cord. In pharmacologic validation studies, rats received morphine, carprofen, or paracetamol 1 hour before, and/or immediately after, surgery. Rats that underwent hernia repair surgery exhibited significantly lower horizontal and vertical activities in the home cage and open field in the early postsurgical period, compared with sham rats or rats that underwent skin incision only. Morphine, carprofen, and paracetamol attenuated the surgery-induced reductions in locomotor activity, to varying degrees. Surgery was associated with significantly increased c-Fos expression in the ipsilateral dorsal horn of the spinal cord, an effect attenuated by carprofen treatment. These results support the development and characterization of a novel, anatomically relevant animal model of acute postoperative pain that may facilitate development of improved treatment regimens.Perspective: Acute pain following inguinal hernia repair can be difficult to treat. Here we report, for the first time, the development of a novel, anatomically relevant rat model to facilitate improved understanding and treatment of acute postoperative pain following inguinal hernia repair. (C) 2015 by the American Pain Society
  • Publication
    Evidence for a role of GABAergic and glutamatergic signalling in the basolateral amygdala in endocannabinoid-mediated fear-conditioned analgesia in rats
    (Elsevier, 2012-12-31) Rea, Kieran; Olango, Weredeselam M.; Harhen, Brendan; Kerr, Daniel M.; Galligan, Rachel; Fitzgerald, Sean; Moore, Maeve; Roche, Michelle; Finn, David P.
    The basolateral amygdala (BLA) is a key substrate facilitating the expression of fear-conditioned analgesia (FCA). However, the neurochemical mechanisms in the BLA which mediate this potent suppression of pain responding during fear remain unknown. The present study investigated the role of cannabinoid(1) (CB1) receptors and interactions with GABAergic (GABA(A) receptor) and glutamatergic (metabotropic glutamate receptor type 5; mGluR5) signalling in the BLA in formalin-evoked nociceptive behaviour and FCA in rats. Reexposure to a context previously paired with foot shock significantly reduced formalin-evoked nociceptive behaviour. Systemic or intra-BLA microinjection of the CB1 receptor antagonist/inverse agonist AM251 prevented this expression of FCA, while injection of AM251 into the central nucleus of the amygdala did not. The suppression of FCA by systemic AM251 administration was partially attenuated by intra-BLA administration of either the GABA(A) receptor antagonist bicuculline or the mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine, (MPEP). Bilateral microinjection of MPEP, but not bicuculline, alone into the BLA enhanced formalin-evoked nociceptive behaviour. Postmortem analyses revealed that FCA was associated with a significant increase in tissue levels of anandamide in the BLA side contralateral to intraplantar formalin injection. In addition, fear-conditioned rats exhibited a robust formalin-induced increase in levels of 2-arachidonyl glycerol and N-palmitoylethanolamide in the ipsilateral and contralateral BLA, respectively. These data suggest that CB1 receptors in the BLA facilitate the expression of FCA, through a mechanism which is likely to involve the modulation of GABAergic and glutamatergic signalling. (c) 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
  • Publication
    The prefrontal cortical endocannabinoid system modulates fear–pain interactions in a subregion‐specific manner
    (Wiley, 2018-05-30) Rea, Kieran; McGowan, Fiona; Corcoran, Louise; Roche, Michelle; Finn, David P.; Science Foundation Ireland; Irish Research Council; College of Medicine, National University of Ireland Galway
    Background and Purpose The emotional processing and coordination of top‐down responses to noxious and conditioned aversive stimuli involves the medial prefrontal cortex (mPFC). Evidence suggests that subregions of the mPFC [infralimbic (IfL), prelimbic (PrL) and anterior cingulate (ACC) cortices] differentially alter the expression of contextually induced fear and nociceptive behaviour. We investigated the role of the endocannabinoid system in the IfL, PrL and ACC in formalin‐evoked nociceptive behaviour, fear‐conditioned analgesia (FCA) and conditioned fear in the presence of nociceptive tone. Experimental Approach FCA was modelled in male Lister‐hooded rats by assessing formalin‐evoked nociceptive behaviour in an arena previously paired with footshock. The effects of intra‐mPFC administration of AM251 [cannabinoid type 1 (CB1) receptor antagonist/inverse agonist], URB597 [fatty acid amide hydrolase (FAAH) inhibitor] or URB597 + AM251 on FCA and freezing behaviour were assessed. Key Results AM251 attenuated FCA when injected into the IfL or PrL and reduced contextually induced freezing behaviour when injected intra‐IfL but not intra‐PrL or intra‐ACC. Intra‐ACC administration of AM251 alone or in combination with URB597 had no effect on FCA or freezing. URB597 attenuated FCA and freezing behaviour when injected intra‐IfL, prolonged the expression of FCA when injected intra‐PrL and had no effect on these behaviours when injected intra‐ACC. Conclusions and Implications These results suggest important and differing roles for FAAH substrates or CB1 receptors in the PrL, IfL and ACC in the expression of FCA and conditioned fear in the presence of nociceptive tone.
  • Publication
    Locomotor and anti-immobility effects of buprenorphine in combination with the opioid receptor modulator samidorphan in rats
    (Elsevier, 2018-12-13) Burke, Nikita N.; Ferdousi, Mehnaz; Deaver, Daniel R.; Finn, David P.; Roche, Michelle; Kelly, John P.; Alkermes Inc; Science Foundation Ireland
    Modulation of the opioid system has re-emerged as a potential therapeutic avenue for treating depression, with efficacy of a fixed-dose combination of buprenorphine (BUP), a partial mu-opioid receptor (MOR) agonist and kappa-opioid receptor (KOR) antagonist, and samidorphan (SAM), a potent MOR antagonist, as an adjuvant treatment in patients with major depressive disorder (MDD). To advance understanding of the mechanism of action underlying this combination, we examined BUP, SAM and their combination in a series of rat behavioural assays. We examined effects on locomotor activity in Sprague Dawley (SD) rats over an extended period of time in a home-cage tracking system, and behavioural despair (immobility) in the forced swim test (FST), a commonly-used test to study antidepressants, in SD and Wistar-Kyoto (WKY) rats. Strain differences in opioid receptor and prepropeptide mRNA expression in the brain (prefrontal cortex, amygdala, hippocampus and striatum) were examined using qRT-PCR. BUP produced locomotor hyperactivity in SD rats from 2 to 6 h following administration, which was attenuated by SAM. In SD rats, a low, but not a high, dose of SAM in combination with BUP counteracted swim-stress induced immobility. This effect was not seen with BUP alone. In contrast, BUP alone reduced immobility in WKY rats, and this effect was enhanced by a low, but not high, dose of SAM. In WKY rats, MOR mRNA expression was higher in the hippocampus and lower in the striatum vs. SD rats. KOR mRNA expression was higher in the amygdala and nociceptin receptor (NOP) mRNA expression was lower in the hippocampus vs. SD rats. Differences in opioid receptor expression may account for the differential behavioural profile of WKY and SD rats. In summary, administration of BUP, a MOR receptor agonist together with a MOR opioid-receptor antagonist, SAM, reduces behavioural despair in animal models traditionally used to study effects of antidepressants.
  • Publication
    Supraspinal Transient Receptor Potential Subfamily V Member 1 (TRPV1) in pain and psychiatric disorders
    (Karger, 2015) Madasu, Manish K.; Roche, Michelle; Finn, David P.; Science Foundation Ireland; College of Science, National University of Ireland, Galway
    The transient receptor potential subfamily V member 1 (TRPV1) belongs to the diverse transient receptor potential (TRP) family of cation channels. It was first characterized in primary afferent fibres as a receptor for capsaicin. Peripheral TRPV1 has a very well-described role in nociception. However, TRPV1 is now recognized to have a broader distribution and function, with supraspinal/brain TRPV1 known to modulate pain processing. Recently, studies employing histological, genetic and pharmacological approaches have provided evidence that supraspinal TRPV1 also modulates brain neurobiology and behaviours related to anxiety, depression and schizophrenia. Key brain regions involved in TRPV1-mediated modulation of pain and affect include the periaqueductal grey, hippocampus and medial prefrontal cortex. Thus, TRPV1 in the brain is emerging as an important molecular substrate which is dually implicated in both pain and psychiatric disorders, and represents a novel therapeutic target for these conditions and their comorbidity. (C) 2015 S. Karger AG, Basel
  • Publication
    Involvement of the endocannabinoid system in attentional modulation of nociceptive behaviour in rats
    (Wiley, 2014-11-15) Ford, Gemma K.; Moriarty, Orla; Okine, Bright N.; Tully, E.; Mulcahy, A.; Harhen, Brendan; Finn, David P.; Science Foundation Ireland
    BackgroundDistraction is used clinically to relieve and manage pain. It is hypothesized that pain demands attention and that exposure to another attention-demanding stimulus causes withdrawal of attention away from painful stimuli, thereby reducing perceived pain. We have recently developed a rat model that provides an opportunity to investigate the neurobiological mechanisms mediating distraction-induced analgesia, as these mechanisms are, at present, poorly understood. Given the well-described role of the endogenous cannabinoid (endocannabinoid; EC) system in the modulation of pain and attentional processing, the present study investigated its role in distraction-induced antinociception in rats.MethodsAnimals received the CB1 receptor antagonist/inverse agonist, rimonabant or vehicle intraperitoneally, 30min prior to behavioural evaluation. Formalin-evoked nociceptive behaviour was measured in the presence or absence of a novel-object distractor. Liquid chromatography-tandem mass spectrometry was used to determine the levels of the endogenous cannabinoids anandamide and 2-arachidonoylglycerol (2-AG) in the ventral hippocampus (vHip).ResultsExposure to a novel object distractor significantly reduced formalin-evoked nociceptive behaviour. The novel object-induced reduction in nociceptive behaviour was attenuated by rimonabant. Novel object exposure was also associated with increased tissue levels of anandamide and 2-AG in the vHip.ConclusionsThese data suggest that the reduction in formalin-evoked nociceptive behaviour that occurs as a result of exposure to a novel object may be mediated by engagement of the EC system, in particular in the vHip. The results provide evidence that the EC system may be an important neural substrate subserving attentional modulation of pain.
  • Publication
    Impaired cued and spatial learning performance and altered cannabinoid CB1 receptor functionality in the substantia nigra in a rat model of diabetic neuropathy
    (Elsevier, 2016-01-13) Moriarty, Orla; Lang, Yvonne; Idrees, Zubair; McGuire, Brian E.; Finn, David P.; Science Foundation Ireland; Higher Education Authority; National Biophotonics and Imaging Platform, Ireland
    Diabetes, and associated diabetic neuropathic pain, impact negatively on cognitive function. However, the underlying mechanisms remain poorly understood. This study investigated neuropathic pain-related behaviour and cognitive function in the rat streptozotocin (STZ) model of diabetes, and assessed cannabinoid(1) (CB1) receptor functionality in discrete brain regions. Male Lister-Hooded rats received STZ (60 mg/kg s.c.) or vehicle. Sensory responses were assessed in von Frey and Hargreaves tests. Cognitive, motor and sensorimotor functions were assessed using novel object recognition and Morris water maze tasks. CB1 receptor functionality was assessed by [S-35]GTP gamma S (guanosine 5'-O-[gamma-thio]triphosphate) autoradiography. STZ treatment was associated with mechanical allodynia and thermal hypoalgesia. Novel object recognition was unaltered in diabetic rats. STZ treatment was associated with impaired performance in the Morris water maze acquisition phase, but there were no differences in memory retrieval in the probe trial. Stimulus-response learning in the water maze cued trial was also disrupted in STZ-treated rats, possibly indicating sensorimotor deficits. CB1 receptor agonist-stimulated [S-35]GTP gamma S binding was attenuated in the substantia nigra of STZ-treated rats but unaltered in the hippocampus. In conclusion, STZ treatment as a model of diabetic neuropathy was associated with specific functional deficits in the Morris water maze, effects which may be related to altered CB1 receptor functionality in the substantia nigra. (C) 2016 Elsevier B.V. All rights reserved.
  • Publication
    Genotype-dependent responsivity to inflammatory pain: A role for TRPV1 in the periaqueductal grey
    (Elsevier, 2016-08-09) Madasu, Manish K.; Okine, Bright N.; Olango, Weredeselam M.; Rea, Kieran; Lenihan, Róisín; Roche, Michelle; Finn, David P.; Science Foundation Ireland; Irish Research Council; College of Science, National University of Ireland, Galway
    Negative affective state has a significant impact on pain, and genetic background is an important moderating influence on this interaction. The Wistar-Kyoto (WKY) inbred rat strain exhibits a stress-hyperresponsive, anxiety/depressive-like phenotype and also displays a hyperalgesic response to noxious stimuli. Transient receptor potential subfamily V member 1 (TRPV1) within the midbrain periaqueductal grey (PAG) plays a key role in regulating both aversive and nociceptive behaviour. In the present study, we investigated the role of TRPV1 in the sub-columns of the PAG in formalin-evoked nociceptive behaviour in WKY versus Sprague-Dawley (SD) rats. TRPV1 mRNA expression was significantly lower in the dorsolateral (DL) PAG and higher in the lateral (L) PAG of WKY rats, compared with SD counterparts. There were no significant differences in TRPV1 mRNA expression in the ventrolateral (VL) PAG between the two strains. TRPV1 mRNA expression significantly decreased in the DLPAG and increased in the VLPAG of SD, but not WKY rats upon intra-plantar formalin administration. Intra-DLPAG administration of either the TRPV1 agonist capsaicin, or the TRPV1 antagonist 5'-lodoresiniferatoxin (5'-IRTX), significantly increased formalin-evoked nociceptive behaviour in SD rats, but not in WKY rats. The effects of capsaicin were likely due to TRPV1 desensitisation, given their similarity to the effects of 5'-IRTX. Intra-VLPAG administration of capsaicin or 5'-IRTX reduced nociceptive behaviour in a moderate and transient manner in SD rats, and similar effects were seen with 5'-IRTX in WKY rats. Intra-LPAG administration of 5'-IRTX reduced nociceptive behaviour in a moderate and transient manner in SD rats, but not in WKY rats. These results indicate that modulation of inflammatory pain by TRPV1 in the PAG occurs in a sub-column-specific manner. The data also provide evidence for differences in the expression of TRPV1, and differences in the effects of pharmacological modulation of TRPV1 in specific PAG sub-columns, between WKY and SD rats, suggesting that TRPV1 expression and/or functionality in the PAG plays a role in hyper-responsivity to noxious stimuli in a genetic background prone to negative affect. (C) 2016 Elsevier Ltd. All rights reserved.
  • Publication
    Impaired recognition memory and cognitive flexibility in the rat L5-L6 spinal nerve ligation model of neuropathic pain
    (De Gruyter, 2016-01-01) Moriarty, Orla; Gorman, Claire L.; McGowan, Fiona; Ford, Gemma K.; Roche, Michelle; Thompson, Kerry; Dockery, Peter; McGuire, Brian E.; Finn, David P.; National Biophotonics and Imaging Platform, Ireland; EU Structural Funds
    Background and aims: Although neuropathic pain is known to negatively affect cognition, the neural mechanisms involved are poorly understood. Chronic pain is associated with changes in synaptic plasticity in the brain which may impact on cognitive functioning. The aim of this study was to model neuropathic pain in mid-aged rats using spinal nerve ligation (SNL). Following establishment of allodynia and hyperalgesia, behaviour was assessed in a battery of cognitive tests. Expression of the presynaptic protein, synaptophysin, and its colocalisation with the vesicular GABA and glutamate transporters (vGAT and vGLUT, respectively), was investigated in the medial prefrontal cortex (mPFC) and hippocampus.Methods: Nine month old male Sprague Dawley rats underwent L5-L6 spinal nerve ligation or a sham procedure. Mechanical and cold allodynia and thermal hyperalgesia were assessed using von Frey, acetone and Hargreaves tests, respectively. Cognition was assessed in the novel-object recognition, air-puff passive avoidance and Morris water maze behavioural tasks. Immunohistochemistry was used to examine the expression of synaptophysin in the mPFC and CA1 region of the hippocampus and double labelling of synaptophysin and the vesicular transporters vGAT and vGlut was used to investigate the distribution of synaptophysin on GABAergic and glutamatergic neurons.Results: SNL rats displayed impaired performance in the novel-object recognition task. Passive-avoidance responding, and spatial learning and memory in the Morris water maze, were unaffected by SNL surgery. However, in the water maze reversal task, pain-related impairments were evident during training and probe trials. SNL surgery was not associated with any differences in the expression of synaptophysin or its colocalisation with vGAT or vGLUT in the mPFC or the hippocampal CA1 region.Conclusions: These results suggest that the SNL model of neuropathic pain is associated with deficits in recognition memory and cognitive flexibility, but these deficits are not associated with altered synaptophysin expression or distribution in the mPFC and CA1.Implications: Cognitive complaints are common amongst chronic pain patients. Here we modelled cognitive impairment in a well-established animal model of neuropathic pain and investigated the neural mechanisms involved. A better understanding of this phenomenon is an important prerequisite for the development of improved treatment of patients affected. (C) 2015 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
  • Publication
    Repeated forced swim stress differentially affects formalin-evoked nociceptive behaviour and the endocannabinoid system in stress normo-responsive and stress hyper-responsive rat strains
    (Elsevier, 2015-05-16) Jennings, Elaine M.; Okine, Bright N.; Olango, Weredeselam M.; Roche, Michelle; Finn, David P.; Science Foundation Ireland; Irish Research Council
    Repeated exposure to a homotypic stressor such as forced swimming enhances nociceptive responding in rats. However, the influence of genetic background on this stress-induced hyperalgesia is poorly understood. The aim of the present study was to compare the effects of repeated forced swim stress on nociceptive responding in Sprague-Dawley (SD) rats versus the Wistar Kyoto (WKY) rat strain, a genetic background that is susceptible to stress, negative affect and hyperalgesia. Given the well-documented role of the endocannabinoid system in stress and pain, we investigated associated alterations in endocannabinoid signalling in the dorsal horn of the spinal cord and amygdala. In SD rats, repeated forced swim stress for 10 days was associated with enhanced late phase formalin-evoked nociceptive behaviour, compared with naive, non-stressed SD controls. In contrast, WKY rats exposed to 10 days of swim stress displayed reduced late phase formalin-evoked nociceptive behaviour. Swim stress increased levels of monoacylglycerol lipase (MAGL) mRNA in the ipsilateral side of the dorsal spinal cord of SD rats, an effect not observed in WKY rats. In the amygdala, swim stress reduced anandamide (AEA) levels in the contralateral amygdala of SD rats, but not WKY rats. Additional within-strain differences in levels of CB1 receptor and fatty acid amide hydrolase (FAAH) mRNA and levels of 2-arachidonylglycerol (2-AG) were observed between the ipsilateral and contralateral sides of the dorsal horn and/or amygdala. These data indicate that the effects of repeated stress on inflammatory pain-related behaviour are different in two rat strains that differ with respect to stress responsivity and affective state and implicate the endocannabinoid system in the spinal cord and amygdala in these differences. (C) 2015 Elsevier Inc. All rights reserved.