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Figure 2 | Molecular Pain

Figure 2

From: Molecular and cellular mechanisms of the age-dependency of opioid analgesia and tolerance

Figure 2

Molecular and cellular mechanisms of the age-dependency of opioid analgesia and tolerance. Mechanisms of opioid analgesia and tolerance at the molecular and cellular levels are complex, and many of them require a modification of the expression and functions of signaling molecules. Aging has a significant impact on almost every aspect of the opioid receptor signaling systems that underlie opioid analgesia and tolerance. Endogenous opioid peptides and opioid receptors are differentially expressed in different developmental stages, and aging is associated with changes in the number and/or affinity of opioid receptors and opioid receptor-like 1 (ORL1). The expression of β-arrestin, which plays a prominent part in opioid receptor desensitization, is determined by neural differentiation and aging. The increased expression of β-arrestin is accompanied by a parallel increase in G protein-coupled receptor kinase (GRK) expression during prenatal development. The phosphorylation of opioid receptors by GRK and the binding of β-arrestin initiate the internalization of the ligand-bound receptors. The internalization of epidermal growth factor (EGF) receptors and interleukin 2 (IL2) receptors and clathrin-associated endocytosis are age-dependent, which implies that the same might be also true for opioid receptor systems. Aging affects the expression and function of the N-methyl-D-aspartic acid (NMDA) receptor and its subunits—calmodulin (CaM) and protein kinase C (PKC) and its various isoforms—as well as other neuropeptides known to have anti-opioid effects. The expression, regulation, and function of specific G protein signaling (RGS) members are affected by age during embryonic development and neuronal differentiation. Development and aging differentially regulate G protein-mediated adenylate cyclase (AC) signaling. The activities of AC, guanylate cyclase (GC), cyclic AMP (cAMP), phosphodiesterase, and cyclic GMP (cGMP) phosphodiesterase in the frontal cortex and cerebellum show age-related changes.

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