Modulation of the Negative Affective Dimension of Pain: Focus on Selected Neuropeptidergic System Contributions

et al. 2023

Preprint

Background and purpouse Psychological disorders, such as anxiety and anhedonia are pain comorbidities, however how pain affects male and female individuals and through which mechanism is not well understood. Previous research show pain-induced alterations in the dynorphinergic pathway in the mesocorticolimbic system (MCLS) together with a relationship between corticotropin-releasing system and dynorphin release in the MCLS. Here, we analyse the sex and time course-dependent effects of pain on negative affect. Additionally, we study the implication of dynorphinergic and corticotropin releasing factor involvement in these pain related behaviours. Experimental approach We used behavioural pharmacology and biochemical tools to characterize negative affective states induced by inflammatory pain in male and female rats, and the alterations in dynorphinergic and corticotropin systems in the MCLS. Key results. Female rats showed a persistent anxiety-like together with a reversible anhedonia-like behaviours derived from inflammatory pain. Additionally, we found alterations of in both dynorphin and corticotropin releasing factor in NAc and amygdala that suggest sex-dependent dynamic adaptations. Finally blockade on the kappa opioid receptor in the NAc confirmed its role in pain-induced anxiety-like behaviour in female rats. Conclusions and implications Our results show sex and time dependent anxiety- and anhedonia-like behaviours induced by the presence of pain in female rats. Furthermore, we replicated previous data pointing to the KOR/dyn recruitment in the NAc as key neurological substrate mediating these behaviours. This research encourages the study the mechanisms underlying these behaviours, to better understand the emotional dimension of pain.

Section: Resultsmentioning

confidence: 99%

Sex-dependent effect of inflammatory pain on negative affective states is prevented by kappa opioid receptors blockade in the nucleus accumbens shell

Lorente

Cuitavi

et al. 2023

Preprint

“…These opioid neuropeptides and their corresponding receptors are widely distributed across the neuraxis, and, in particular, in pain pathways [ 23 ]. Additionally, evidence showed that they also participate in the control of many different functions, such as stress responses, depression, anxiety, reward/aversion behavioral response, gastrointestinal transit, and the neuroendocrine and immune functions [ 26 – 28 ]. Upon agonist activation, either endogenous or exogenous, the inhibitory G proteins (Gαi–Gαo) dissociate and subsequently engage a variety of effectors that induce neuronal depression [ 24 ], through the inhibition of adenylate cyclase and ion channel modulation [ 29 , 30 ].…”

Section: Endogenous Opioid Systemmentioning

confidence: 99%

Current and Future Therapeutic Options in Pain Management: Multi-mechanistic Opioids Involving Both MOR and NOP Receptor Activation

Coluzzi

Scerpa³

et al. 2022

CNS Drugs

Self Cite

Opioids are widely used in chronic pain management, despite major concerns about their risk of adverse events, particularly abuse, misuse, and respiratory depression from overdose. Multi-mechanistic opioids, such as tapentadol and buprenorphine, have been widely studied as a valid alternative to traditional opioids for their safer profile. Special interest was focused on the role of the nociceptin opioid peptide (NOP) receptor in terms of analgesia and improved tolerability. Nociceptin opioid peptide receptor agonists were shown to reinforce the antinociceptive effect of mu opioid receptor (MOR) agonists and modulate some of their adverse effects. Therefore, multi-mechanistic opioids involving both MOR and NOP receptor activation became a major field of pharmaceutical and clinical investigations. Buprenorphine was re-discovered in a new perspective, as an atypical analgesic and as a substitution therapy for opioid use disorders; and buprenorphine derivatives have been tested in animal models of nociceptive and neuropathic pain. Similarly, cebranopadol, a full MOR/NOP receptor agonist, has been clinically evaluated for its potent analgesic efficacy and better tolerability profile, compared with traditional opioids. This review overviews pharmacological mechanisms of the NOP receptor system, including its role in pain management and in the development of opioid tolerance. Clinical data on buprenorphine suggest its role as a safer alternative to traditional opioids, particularly in patients with non-cancer pain; while data on cebranopadol still require phase III study results to approve its introduction on the market. Other bifunctional MOR/NOP receptor ligands, such as BU08028, BU10038, and AT-121, are currently under pharmacological investigations and could represent promising analgesic agents for the future.

“…Overall ANOVA revealed a significant effect of strain on the pN/OFQ gene expression [F (1,20) = 16.17, p = 0.0007]; no significant effect of EtOH drinking [F (1,20) = 2.510, p = 0.1288, n.s.] and of strain × EtOH drinking interaction [F (1,20) = 2.731, p = 0.1140, n.s.]…”

Section: Pn/ofq Expressionmentioning

confidence: 99%

“…Moreover, we decided to expand our analysis to the corticotropin-releasing factor (CRF)–CRF receptor 1 (CRF1R) as it is tightly linked to the regulation of the above mentioned opioidergic mechanisms. In fact, it is well known that both CRFergic and DYNergic transmissions mediate stress response and contribute to the expression of negative reinforcement [ 18 , 19 , 20 , 21 ]. Whereas, activation of NOP by N/OFQ results in a functional CRF antagonism and mediates anti-stress responses [ 19 , 22 , 23 , 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

“…We focused our attention to the AMY and the bed nucleus of the stria terminalis (BNST), as these regions represent important crossroads where mechanisms regulating reward, stress and addiction intersect each other [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. Besides the analysis of basal gene expression for the above mentioned systems, we also evaluated how the chronic intermittent consumption of alcohol (CIE), a well characterized animal model of binge drinking in humans [ 35 , 36 , 37 ], may impact on the expression of the investigated neuropeptidergic systems in msP or Wistar rats.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Dysregulation of Nociceptin/Orphanin FQ and Dynorphin Systems in the Extended Amygdala of Alcohol Preferring Marchigian Sardinian (msP) Rats

Caputi

Stopponi

et al. 2021

IJMS

Self Cite

Previous studies have shown that genetically selected Marchigian Sardinian alcohol-preferring (msP) rats consume excessive amounts of ethanol to self-medicate from negative moods and to relieve innate hypersensitivity to stress. This phenotype resembling a subset of alcohol use disorder (AUD) patients, appears to be linked to a dysregulation of the equilibrium between stress and antistress mechanisms in the extended amygdala. Here, comparing water and alcohol exposed msP and Wistar rats we evaluate the transcript expression of the anti-stress opioid-like peptide nociceptin/orphanin FQ (N/OFQ) and its receptor NOP as well as of dynorphin (DYN) and its cognate κ-opioid receptor (KOP). In addition, we measured the transcript levels of corticotropin-releasing factor (CRF), CRF receptor 1 (CRF1R), brain-derived neurotrophic factor (BDNF) and of the tropomyosin receptor kinase B receptor (Trk-B). Results showed an innately up-regulation of the CRFergic system, mediating negative mood and stress responses, as well as an inherent up-regulation of the anti-stress N/OFQ system, both in the amygdala (AMY) and bed nucleus of the stria terminalis (BNST) of msP rats. The up-regulation of this latter system may reflect an attempt to buffer the negative condition elicited by the hyperactivity of pro-stress mechanisms since results showed that voluntary alcohol consumption dampened N/OFQ. Alcohol exposure also reduced the expression of dynorphin and CRF transmissions in the AMY of msP rats. In the BNST, alcohol intake led to a more complex reorganization of these systems increasing receptor transcripts in msP rats, along with an increase of CRF and a decrease of N/OFQ transcripts, respectively. Moreover, mimicking the effects of alcohol in the AMY we observed that the activation of NOP receptor by intracerebroventricular administration of N/OFQ in msP rats caused an increase of BDNF and a decrease of CRF transcripts. Our study indicates that both stress and anti-stress mechanisms are dysregulated in the extended AMY of msP rats. The voluntary alcohol drinking, as well as NOP agonism, have a significant impact on neuropeptidergic systems arrangement, bringing the systems back to normalization.