Regulation and Functional Implications of Opioid Receptor Splicing in Opioid Pharmacology and HIV Pathogenesis

Abstract

Despite the identification and characterization of four opioid receptor subtypes and the genes from which they are encoded, pharmacological data does not conform to the predications of a four opioid receptor model. Instead, current studies of opioid pharmacology suggest the existence of additional receptor subtypes; however, no additional opioid receptor subtype has been identified to date. It is now understood that this discrepancy is due to the generation of multiple isoforms of opioid receptor subtypes. While several mechanisms are utilized to generate these isoforms, the primary mechanism involves alternative splicing of the pre-mRNA transcript. Extensive alternative splicing patterns for opioid receptors have since been identified and discrepancies in opioid pharmacology are now partially attributed to variable expression of these isoforms. Recent studies have been successful in characterizing the localization of these isoforms as well as their specificity in ligand binding; however, the regulation of opioid receptor splicing specificity is poorly characterized. Furthermore, the functional significance of individual receptor isoforms and the extent to which opioid- and/or HIV-mediated changes in the opioid receptor isoform profile contributes to altered opioid pharmacology or the well-known physiological role of opioids in the exacerbation of HIV neurocognitive dysfunction is unknown. As such, the current review details constitutive splicing mechanisms as well as the specific architecture of opioid receptor genes, transcripts, and receptors in order to highlight the current understanding of opioid receptor isoforms, potential mechanisms of their regulation and signaling, and their functional significance in both opioid pharmacology and HIV-associated neuropathology.

Kappa opioid receptor signaling protects cartilage tissue against posttraumatic degeneration

“…The degradation of GAGs in cartilage matrix was assessed after safranin O staining of sections following OARSI recommendations (21). Three sections from every mouse specimen were scored by 3 blinded researchers.…”

Escalating morphine dosing in HIV-1 Tat transgenic mice with sustained Tat exposure reveals an allostatic shift in neuroinflammatory regulation accompanied by increased neuroprotective non-endocannabinoid lipid signaling molecules and amino acids

“…In vivo and in vitro studies focusing on the HIV-1 transactivator of transcription (Tat) protein demonstrate morphine’s exacerbating effects on microglial activation [ 25 – 29 ], astroglia dysregulation [ 29 – 32 ], cytokine production [ 33 – 38 ], and blood-brain barrier (BBB) breakdown [ 13 , 39 , 40 ], with additional effects on oxidative stress [ 33 , 34 , 41 , 42 ], intracellular calcium [ 34 , 37 , 43 ], and neurotoxicity [ 38 , 42 – 44 ], potentially due to morphine’s action on μ-opioid receptor (MOR)-expressing glia [ 31 , 45 ]. Notably, HIV-1 and HIV-1 proteins, such as Tat, impact opioid gene expression and splicing specificity [ 38 , 46 – 48 ], potentially mediated through the release of various proinflammatory cytokines, including IL-6, TNF, GM-CSF, and IFN-γ [ 49 , 50 ]. Further, the proinflammatory effects of HIV-1 Tat at C-C chemokine receptor type 5 (CCR5) desensitize MOR or δ-opioid receptors (DOR [ 51 – 53 ]), an effect that appears to contribute to decreased antinociceptive potency of morphine in Tat transgenic mice [ 54 ].…”

Kappa Opioid Receptor signaling protects cartilage tissue against posttraumatic degeneration

“…OARSI scoring and chondrocyte number counting. The degradation of GAGs in cartilage matrix was assessed after safranin O staining of sections following OARSI recommendations (21). Three sections from every mouse specimen were scored by 3 blinded researchers.…”