Clinician's Commentary on Desveaux et al.

Lowery, Carol Damp

doi:10.3138/ptc.2011-42-cc

“…Self-awareness of leadership capabilities is an essential step that will allow physiotherapists to pursue leadership roles in the health care system. 43 …”

Section: Discussionmentioning

confidence: 99%

Perceptions of Leadership: Comparing Canadian and Irish Physiotherapists' Views

McGowan

¹

,

Martin

²

,

Stokes

³

2016

Physiotherapy Canada

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Purpose: To contribute to the growing body of research on leadership in physiotherapy by comparing leadership-related perceptions of physiotherapists in Ireland and in Canada. Methods: This article compares the results of a survey of Canadian physiotherapists with those of the same survey administered to Irish physiotherapists. The results of both studies have previously been reported and are used here to allow a cultural comparison of the perceptions of physiotherapists. The present study used two-portion Z-tests to compare the percentage of physiotherapists in Ireland who self-declared as a leader with the percentage of physiotherapists in Canada who did so. Results: Physiotherapists in both Ireland and Canada most often rated communication and professionalism as extremely important characteristics. Physiotherapists in Canada were more likely than those in Ireland to perceive themselves as leaders (Z=2.67, p < 0.05; 95% CI: 1.33, 9.87). Factors associated with self-declaration as a leader differed between the two countries. Conclusion: Physiotherapists in Canada and Ireland showed both similarities and differences in their perceptions of leadership characteristics. Results from this study may aid the development of future leadership training programmes specifically targeted at physiotherapists.

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“…Other mixed ligands with less or no KOPr activity are discussed here. It has been reported in the literature that the co-administration of DOPr agonist with a MOPr agonist reduces the development of tolerance and dependence on MOPr agonists without attenuating MOPrmediated analgesia, and co-administration of DOPr antagonist with a MOPr agonist also decreases the adverse effects typically associated with MOPr agonists (Li et al, 2012;Lowery et al, 2011). Hence, mixed MOPr/DOPr ligands have been explored previously (Dietis et al, 2009;Horan et al, 1993;Martin et al, 2000;Zielińska et al, 2016) (see Table 1.2 for details).…”

Section: Other Mixed Ligandsmentioning

confidence: 99%

Investigating the anti-cocaine, anti-nociceptive properties and side effects of MP1104, a novel mixed opioid receptor agonist

Atigari¹

0

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<p>Rationale: Drug addiction is a chronic, relapsing disease with great socioeconomic and morbidity costs. There are limited treatments, with no Food and Drug Administration approved pharmacotherapies available for psychostimulant addiction. In addition, the use of prescription opioid medications has reached epidemic proportions in the world. More than 40,000 deaths from prescription opioid overdose was reported in USA alone in the year 2017. There is an urgent need for the development of effective, non-addictive pain medications and addiction treatments. The opioid receptors play an important role in the modulation of pain and addiction. Mu opioid receptor (MOPr) agonists are widely used to treat pain, however, can also induce respiratory depression, tolerance and addiction. In contrast, drugs activating the kappa opioid receptor (KOPr) attenuate the rewarding properties of drugs, hence are promising non-addictive analgesics. However, side effects like aversion, sedation, anxiety and depression limit their clinical utility. Delta opioid receptor (DOPr) agonists have rewarding, anti-nociceptive and anti-depressive properties, but can also cause seizures. We hypothesise that development of mixed opioid receptor ligands may have therapeutic properties with reduced side effects. Therefore, this thesis evaluated MP1104, a potent mixed opioid receptor agonist, with full efficacy at all three receptors and 3- and 13-fold higher binding affinity for KOPr compared to MOPr and DOPr, respectively. MP1104 was evaluated for the ability to modulate cocaine-induced behaviours, the anti-nociceptive effects and side effects. Methods: Male Sprague-Dawley rats were used to investigate the effects of acute MP1104 treatment on cocaine self-administration and drug seeking behaviour. To determine the mechanism, the modulatory effect of MP1104 on dopamine transporter (DAT) function was assessed using rotating disk electrode voltammetry to measure dopamine uptake in rat dorsal striatum (dStr) and nucleus accumbens (NAc) tissue. Evaluation of side effects included sedation (spontaneous locomotor activity), anxiety (elevated plus maze (EPM)), aversion (conditioned place aversion (CPA)) and depression (forced swim tests (FST)) in rats. The anti-nociceptive effects were measured in the warm-water tail withdrawal assay in rats and male C57BL/6 mice. Acute and chronic administration of MP1104 were evaluated in the paclitaxel-induced neuropathic pain model in mice. Results: In rats trained to self-administer cocaine, acute MP1104 (0.3 and 1 mg/kg, i.p.) administration reduced cocaine-primed reinstatement of drug seeking behaviour and caused a significant downward shift in the cocaine dose-response curve. The anti-cocaine effects exerted by MP1104 are in part due to increased dopamine uptake by DAT in the NAc, which was KOPr-mediated. In the warm-water tail withdrawal assay in rats, acute administration of MP1104 (0.3 and 0.6 mg/kg, i.p.) was 4 times longer acting (8 h) than morphine (2 h). These effects were both KOPr and DOPr dependent. In the dose-response tail withdrawal assay, MP1104 was found to be potent in both rats (ED₅₀ = 0.58 mg/kg, s.c.) and mice (ED₅₀ = 0.35 mg/kg, s.c.). In the paclitaxel-induced neuropathic pain model, mice treated with MP1104 showed potent reductions in both mechanical (ED₅₀ = 0.449 mg/kg, s.c.) and cold (ED₅₀ = 0.479 mg/kg, s.c.) allodynia compared to morphine. Following chronic daily administration of the ED₈₀ dose, MP1104 (1.2 mg/kg, i.p.) was more potent than morphine in reducing mechanical and cold allodynia. Surprisingly, MP1104 reversed responding back to baseline (non-disease) levels. The most remarkable finding was that MP1104, unlike morphine did not produce tolerance when administered chronically. When the side effects of MP1104 were evaluated in rats, no significant anxiogenic effects were seen in the EPM, nor pro-depressive effects in the FST, nor aversion in CPA tests in rats. Furthermore, pre-treatment with a DOPr antagonist, led to MP1104 producing aversive effects. This data suggests that the DOPr agonist actions of MP1104 attenuate the KOPr-mediated aversive effects of MP1104. However, at higher doses, MP1104 (1 mg/kg, i.p.) was found to be sedative. Conclusions: MP1104 exerts potent anti-cocaine properties in self-administration tests. The reduced cocaine reward is at least in part due to the ability of MP1104 to modulate DAT function by increasing dopamine uptake in the NAc. MP1104 is also a potent and long-lasting anti-nociceptive agent in rats. Significantly, when evaluated in a chronic neuropathic pain model, MP1104 was potent with no tolerance to the anti-nociceptive effects observed. Moreover, MP1104 showed fewer side effects with reduced sedative effects and no observed anxiety, aversive, nor pro-depressive effects, unlike pure KOPr agonists. This data supports the therapeutic development of mixed opioid receptor agonists, particularly mixed KOPr/DOPr agonists as non-addictive pain medications and anti-cocaine pharmacotherapies with fewer side effects.</p>

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“…Other mixed ligands with less or no KOPr activity are discussed here. It has been reported in the literature that the co-administration of DOPr agonist with a MOPr agonist reduces the development of tolerance and dependence on MOPr agonists without attenuating MOPrmediated analgesia, and co-administration of DOPr antagonist with a MOPr agonist also decreases the adverse effects typically associated with MOPr agonists (Li et al, 2012;Lowery et al, 2011). Hence, mixed MOPr/DOPr ligands have been explored previously (Dietis et al, 2009;Horan et al, 1993;Martin et al, 2000;Zielińska et al, 2016) (see Table 1.2 for details).…”

Section: Other Mixed Ligandsmentioning

confidence: 99%

Investigating the anti-cocaine, anti-nociceptive properties and side effects of MP1104, a novel mixed opioid receptor agonist

Atigari¹

0

View full text Add to dashboard Cite

<p>Rationale: Drug addiction is a chronic, relapsing disease with great socioeconomic and morbidity costs. There are limited treatments, with no Food and Drug Administration approved pharmacotherapies available for psychostimulant addiction. In addition, the use of prescription opioid medications has reached epidemic proportions in the world. More than 40,000 deaths from prescription opioid overdose was reported in USA alone in the year 2017. There is an urgent need for the development of effective, non-addictive pain medications and addiction treatments. The opioid receptors play an important role in the modulation of pain and addiction. Mu opioid receptor (MOPr) agonists are widely used to treat pain, however, can also induce respiratory depression, tolerance and addiction. In contrast, drugs activating the kappa opioid receptor (KOPr) attenuate the rewarding properties of drugs, hence are promising non-addictive analgesics. However, side effects like aversion, sedation, anxiety and depression limit their clinical utility. Delta opioid receptor (DOPr) agonists have rewarding, anti-nociceptive and anti-depressive properties, but can also cause seizures. We hypothesise that development of mixed opioid receptor ligands may have therapeutic properties with reduced side effects. Therefore, this thesis evaluated MP1104, a potent mixed opioid receptor agonist, with full efficacy at all three receptors and 3- and 13-fold higher binding affinity for KOPr compared to MOPr and DOPr, respectively. MP1104 was evaluated for the ability to modulate cocaine-induced behaviours, the anti-nociceptive effects and side effects. Methods: Male Sprague-Dawley rats were used to investigate the effects of acute MP1104 treatment on cocaine self-administration and drug seeking behaviour. To determine the mechanism, the modulatory effect of MP1104 on dopamine transporter (DAT) function was assessed using rotating disk electrode voltammetry to measure dopamine uptake in rat dorsal striatum (dStr) and nucleus accumbens (NAc) tissue. Evaluation of side effects included sedation (spontaneous locomotor activity), anxiety (elevated plus maze (EPM)), aversion (conditioned place aversion (CPA)) and depression (forced swim tests (FST)) in rats. The anti-nociceptive effects were measured in the warm-water tail withdrawal assay in rats and male C57BL/6 mice. Acute and chronic administration of MP1104 were evaluated in the paclitaxel-induced neuropathic pain model in mice. Results: In rats trained to self-administer cocaine, acute MP1104 (0.3 and 1 mg/kg, i.p.) administration reduced cocaine-primed reinstatement of drug seeking behaviour and caused a significant downward shift in the cocaine dose-response curve. The anti-cocaine effects exerted by MP1104 are in part due to increased dopamine uptake by DAT in the NAc, which was KOPr-mediated. In the warm-water tail withdrawal assay in rats, acute administration of MP1104 (0.3 and 0.6 mg/kg, i.p.) was 4 times longer acting (8 h) than morphine (2 h). These effects were both KOPr and DOPr dependent. In the dose-response tail withdrawal assay, MP1104 was found to be potent in both rats (ED₅₀ = 0.58 mg/kg, s.c.) and mice (ED₅₀ = 0.35 mg/kg, s.c.). In the paclitaxel-induced neuropathic pain model, mice treated with MP1104 showed potent reductions in both mechanical (ED₅₀ = 0.449 mg/kg, s.c.) and cold (ED₅₀ = 0.479 mg/kg, s.c.) allodynia compared to morphine. Following chronic daily administration of the ED₈₀ dose, MP1104 (1.2 mg/kg, i.p.) was more potent than morphine in reducing mechanical and cold allodynia. Surprisingly, MP1104 reversed responding back to baseline (non-disease) levels. The most remarkable finding was that MP1104, unlike morphine did not produce tolerance when administered chronically. When the side effects of MP1104 were evaluated in rats, no significant anxiogenic effects were seen in the EPM, nor pro-depressive effects in the FST, nor aversion in CPA tests in rats. Furthermore, pre-treatment with a DOPr antagonist, led to MP1104 producing aversive effects. This data suggests that the DOPr agonist actions of MP1104 attenuate the KOPr-mediated aversive effects of MP1104. However, at higher doses, MP1104 (1 mg/kg, i.p.) was found to be sedative. Conclusions: MP1104 exerts potent anti-cocaine properties in self-administration tests. The reduced cocaine reward is at least in part due to the ability of MP1104 to modulate DAT function by increasing dopamine uptake in the NAc. MP1104 is also a potent and long-lasting anti-nociceptive agent in rats. Significantly, when evaluated in a chronic neuropathic pain model, MP1104 was potent with no tolerance to the anti-nociceptive effects observed. Moreover, MP1104 showed fewer side effects with reduced sedative effects and no observed anxiety, aversive, nor pro-depressive effects, unlike pure KOPr agonists. This data supports the therapeutic development of mixed opioid receptor agonists, particularly mixed KOPr/DOPr agonists as non-addictive pain medications and anti-cocaine pharmacotherapies with fewer side effects.</p>

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Clinician's Commentary on Desveaux et al.

Cited by 3 publications

References 1 publication

Perceptions of Leadership: Comparing Canadian and Irish Physiotherapists' Views

Perceptions of Leadership: Comparing Canadian and Irish Physiotherapists' Views

Investigating the anti-cocaine, anti-nociceptive properties and side effects of MP1104, a novel mixed opioid receptor agonist

Investigating the anti-cocaine, anti-nociceptive properties and side effects of MP1104, a novel mixed opioid receptor agonist

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