A novel inhibitor of endocannabinoid catabolic enzymes sheds light on behind the scene interplay between chronic pain, analgesic tolerance, and heroin dependence

Certain types of nonpsychoactive cannabinoids can potentiate glycine receptors (GlyRs), an important target for nociceptive regulation at the spinal level. However, little is known about the potential and mechanism of glycinergic cannabinoids for chronic pain treatment. We report that systemic and intrathecal administration of cannabidiol (CBD), a major nonpsychoactive component of marijuana, and its modified derivatives significantly suppress chronic inflammatory and neuropathic pain without causing apparent analgesic tolerance in rodents. The cannabinoids significantly potentiate glycine currents in dorsal horn neurons in rat spinal cord slices. The analgesic potency of 11 structurally similar cannabinoids is positively correlated with cannabinoid potentiation of the α3 GlyRs. In contrast, the cannabinoid analgesia is neither correlated with their binding affinity for CB1 and CB2 receptors nor with their psychoactive side effects. NMR analysis reveals a direct interaction between CBD and S296 in the third transmembrane domain of purified α3 GlyR. The cannabinoid-induced analgesic effect is absent in mice lacking the α3 GlyRs. Our findings suggest that the α3 GlyRs mediate glycinergic cannabinoid-induced suppression of chronic pain. These cannabinoids may represent a novel class of therapeutic agents for the treatment of chronic pain and other diseases involving GlyR dysfunction.

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Involvement of P2X7 receptors in chronic pain disorders

Purinergic Signalling ◽

10.1007/s11302-021-09796-5 ◽

2021 ◽

Author(s):

Wen-Jing Ren ◽

Peter Illes

Keyword(s):

Chronic Pain ◽

Bacterial Infections ◽

Primary Headache ◽

Cellular Damage ◽

Immune Functions ◽

P2x7 Receptors ◽

Analgesic Tolerance ◽

Intracellular Space ◽

Pannexin 1 ◽

Molecular Patterns

AbstractChronic pain is caused by cellular damage with an obligatory inflammatory component. In response to noxious stimuli, high levels of ATP leave according to their concentration gradient, the intracellular space through discontinuities generated in the plasma membrane or diffusion through pannexin-1 hemichannels, and activate P2X7Rs localized at peripheral and central immune cells. Because of the involvement of P2X7Rs in immune functions and especially the initiation of macrophage/microglial and astrocytic secretion of cytokines, chemokines, prostaglandins, proteases, reactive oxygen, and nitrogen species as well as the excitotoxic glutamate/ATP, this receptor type has a key role in chronic pain processes. Microglia are equipped with a battery of pattern recognition receptors that detect pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) from bacterial infections or danger associated molecular patterns (DAMPs) such as ATP. The co-stimulation of these receptors leads to the activation of the NLRP3 inflammasome and interleukin-1β (IL-1β) release. In the present review, we invite you to a journey through inflammatory and neuropathic pain, primary headache, and regulation of morphine analgesic tolerance, in the pathophysiology of which P2X7Rs are centrally involved. P2X7R bearing microglia and astrocyte-like cells playing eminent roles in chronic pain will be also discussed.

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Sex Differences in Tolerance to Delta-9-Tetrahydrocannabinol in Mice With Cisplatin-Evoked Chronic Neuropathic Pain

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.684115 ◽

2021 ◽

Vol 8 ◽

Author(s):

Angela N. Henderson-Redmond ◽

LaTaijah C. Crawford ◽

Diana E. Sepulveda ◽

David E. Hale ◽

Julia J. Lesperance ◽

...

Keyword(s):

Chronic Pain ◽

Sex Differences ◽

Neuropathic Pain ◽

Cannabinoid Receptor ◽

Therapeutic Potential ◽

Preclinical Research ◽

Chronic Neuropathic Pain ◽

Analgesic Tolerance ◽

Increased Sensitivity ◽

Males And Females

Tolerance to the pain-relieving effects of cannabinoids limits the therapeutic potential of these drugs in patients with chronic pain. Recent preclinical research with rodents and clinical studies in humans has suggested important differences between males and females in the development of tolerance to cannabinoids. Our previous work found that male mice expressing a desensitization resistant form (S426A/S430A) of the type 1 cannabinoid receptor (CB1R) show delayed tolerance and increased sensitivity to the antinociceptive effects of delta-9-tetrahydrocannabinol (∆9-THC). Sex differences in tolerance have been reported in rodent models with females acquiring tolerance to ∆9-THC faster than males. However, it remains unknown whether the S426A/S430A mutation alters analgesic tolerance to ∆9-THC in mice with chemotherapy-evoked chronic neuropathic pain, and also whether this tolerance might be different between males and females. Male and female S426A/S430A mutant and wild-type littermates were made neuropathic using four once-weekly injections of 5 mg/kg cisplatin and subsequently assessed for tolerance to the anti-allodynic effects of 6 and/or 10 mg/kg ∆9-THC. Females acquired tolerance to the anti-allodynic effects of both 6 and 10 mg/kg ∆9-THC faster than males. In contrast, the S426A/S430A mutation did not alter tolerance to ∆9-THC in either male or female mice. The anti-allodynic effects of ∆9-THC were blocked following pretreatment with the CB1R antagonist, rimonabant, and partially blocked following pretreatment with the CB2R inverse agonist, SR144528. Our results show that disruption of the GRK/β-arrestin-2 pathway of desensitization did not affect sensitivity and/or tolerance to ∆9-THC in a chronic pain model of neuropathy.

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Morphine induces dysfunction of PINK1/Parkin-mediated mitophagy in spinal cord neurons implying involvement in antinociceptive tolerance

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjz002 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1056-1068 ◽

Cited By ~ 5

Author(s):

Hong Kong ◽

Chun-Yi Jiang ◽

Liang Hu ◽

Peng Teng ◽

Yan Zhang ◽

...

Keyword(s):

Chronic Pain ◽

Chronic Administration ◽

Morphine Tolerance ◽

Ros Production ◽

Autophagy Flux ◽

Analgesic Tolerance ◽

Spinal Cord Neurons ◽

Sequestosome 1 ◽

Clinical Challenge

Abstract The development of opioid-induced analgesic tolerance is a clinical challenge in long-term use for managing chronic pain. The mechanisms of morphine tolerance are poorly understood. Mitochondria-derived reactive oxygen species (ROS) is a crucial signal inducing analgesic tolerance and pain. Chronic administration of morphine leads to robust ROS production and accumulation of damaged mitochondria, which are immediately removed by mitophagy. Here, we show that morphine inhibits mitochondria damage-induced accumulation of PTEN-induced putative kinase 1 (PINK1) in neurons. It interrupts the recruitment of Parkin to the impaired mitochondria and inhibits the ubiquitination of mitochondrial proteins catalyzed by Parkin. Consequently, morphine suppresses the recognition of autophagosomes to the damaged mitochondria mediated by LC3 and sequestosome-1 (SQSTM1/p62). Thus, morphine inhibits autophagy flux and leads to the accumulation of SQSTM1/p62. Finally, the impaired mitochondria cannot be delivered to lysosomes for degradation and ultimately induces robust ROS production and morphine tolerance. Our findings suggest that the dysfunction of mitophagy is involved in morphine tolerance. The deficiency of PINK1/Parkin-mediated clearance of damaged mitochondria is crucial for the generation of excessive ROS and important to the development of analgesic tolerance. These findings suggest that the compounds capable of stabilizing PINK1 or restoring mitophagy may be utilized to prevent or reduce opioid tolerance during chronic pain management.

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Opioid Analgesia and Opioid-Induced Adverse Effects: A Review

Pharmaceuticals ◽

10.3390/ph14111091 ◽

2021 ◽

Vol 14 (11) ◽

pp. 1091

Author(s):

Alok K. Paul ◽

Craig M. Smith ◽

Mohammed Rahmatullah ◽

Veeranoot Nissapatorn ◽

Polrat Wilairatana ◽

...

Keyword(s):

Chronic Pain ◽

Adverse Effects ◽

Adverse Reactions ◽

Analgesic Tolerance ◽

Opioid Ligands ◽

Effective Therapeutic Strategy ◽

Μ Opioid Receptor ◽

Repeated Use ◽

Opioid Receptor Agonists ◽

Underlying Pathophysiology

Opioids are widely used as therapeutic agents against moderate to severe acute and chronic pain. Still, these classes of analgesic drugs have many potential limitations as they induce analgesic tolerance, addiction and numerous behavioural adverse effects that often result in patient non-compliance. As opium and opioids have been traditionally used as painkillers, the exact mechanisms of their adverse reactions over repeated use are multifactorial and not fully understood. Older adults suffer from cancer and non-cancer chronic pain more than younger adults, due to the physiological changes related to ageing and their reduced metabolic capabilities and thus show an increased number of adverse reactions to opioid drugs. All clinically used opioids are μ-opioid receptor agonists, and the major adverse effects are directly or potentially connected to this receptor. Multifunctional opioid ligands or peripherally restricted opioids may elicit fewer adverse effects, as shown in preclinical studies, but these results need reproducibility from further extensive clinical trials. The current review aims to overview various mechanisms involved in the adverse effects induced by opioids, to provide a better understanding of the underlying pathophysiology and, ultimately, to help develop an effective therapeutic strategy to better manage pain.

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