Mu and Delta Opioid Receptor Targeting Reduces Connexin 43-Based Heterocellular Coupling during Neuropathic Pain.

Abstract

Chronic neuropathic pain emerges from either central or peripheral lesions inducing spontaneous or amplified responses to non-noxious stimuli. Despite different pharmacological approaches to treat such a chronic disease, neuropathic pain still represents an unmet clinical need, due to long-term therapeutic regimens and severe side effects that limit application of currently available drugs. A critical phenomenon involved in central sensitization is the exchange of signalling molecules and cytokines, between glia and neurons, driving the chronicization process. Herein, using a chronic constriction injury (CCI) model of neuropathic pain, we evaluated the efficacy of the mu (M-) and delta (D-) opioid receptor (-OR) targeting agent LP2 in modulating connexin-based heterocellular coupling and cytokine levels. We found that long-term efficacy of LP2 is consequent to MOR-DOR targeting resulting in the reduction of CCI-induced astrocyte-to-microglia heterocellular coupling mediated by connexin 43. We also found that single targeting of DOR reduces TNF and IL-6 levels in the chronic phase of the disease, but the peripheral and central discharge as the primary source of excitotoxic stimulation in the spinal cord requires a simultaneous MOR-DOR targeting to reduce CCI-induced neuropathic pain.

• Authors: Nunzio Vicario, Simona Denaro, Rita Turnaturi, Lucia Longhitano, Federica Maria Spitale, Salvatore Spoto, Agostino Marrazzo, Agata Zappalà, Daniele Tibullo, Giovanni Li Volti, Santina Chiechio, Lorella Pasquinucci, Rosalba Parenti, Carmela Parenti
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 11 (May 24 2022) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 35682543 (Publication Type: Journal Article)

Chemical References

• Analgesics, Opioid
• Connexin 43
• Receptors, Opioid
• Receptors, Opioid, delta
• Receptors, Opioid, mu

Topics

• Analgesics, Opioid (pharmacology)
• Connexin 43 (therapeutic use)
• Humans
• Hyperalgesia (drug therapy)
• Neuralgia (drug therapy)
• Receptors, Opioid
• Receptors, Opioid, delta
• Receptors, Opioid, mu
• Spinal Cord