Opioid Activation of Toll-Like Receptor 4 Contributes to Drug Reinforcement

Dear Editor,

After having read this interesting article about TLR4-MyD88 dependent signaling and its role in the central proinflammatory immune response to drug reward, I would like to discuss the influence and role of proline-rich peptidic sequences, present in the adapter-accessory/scaffolding proteins at opioid and Toll-Like 4 receptor signaling complexes in inmuno-brain loop (particularly immune-opioid loop) communication.

We know that mental illnesses induce alterations of immune function, and immune system disorders cause changes in behavior. For example, SSRI, SNRI and tricyclic antidepressants, acting on serotonin, dopamine, and norepinephrine receptors, have been shown to possess immunomodulatory and antinflammatory effects in processes governed by pro-inflammatory cytokines. We do not know the full extent of these interrelationships in normal and pathophysiological states, however.

Moreover, as an integrated system, the immune system responds to a number of signals that originate in the neuroendocrine system, and the immunomodulatory potency of hormones and neuropeptides have been extensively described by several authors. These communication routes are characterized by common receptors for cytokines, hormones, and neuropeptides present on cells of both the immune and nervous systems.

Given that opioid receptors are expressed in peripheral afferent nerves and the antibodies against membrane and intracellular autoantigens have been observed in healthy people(Mace et al., 2002), and that TLR4 receptors responding to specific ligands produce proinflammatory mediators and play a critical role in innate immunity and affect adaptive immunity, the endogenous opioid system constitutes a good model for study a neuroimmunologic relationship.

Regarding this point, having evaluated the 100 SNPs most closely associated with disease in schizophrenic patients (Need, et al., 2009), we concluded that these polymorphisms affected proline-containing peptidic sequences present in different adapter-accessory/scaffolding protein isoforms of the neurological and immunological receptor signalling complexes(Lozano et al., 2012).

Adapter-accessory/scaffolding proteins are important modulators of opioid receptor-agonist signaling, either by inhibiting OP-stimulated G protein activation or by associating with a signal transduction mechanism, in which proteins to OP-mediated stimulation of ERK/MAPK containing a SH3 domain that interacts with the proline-rich N-terminus of the scaffold protein RanBPM (Talbot et al., 2009). In signal transduction of TLR4, through a MyD88-dependent pathway, a proline-rich SH3-binding motif in TRAF6 interacts directly with activated SFKs to couple LPS engagement of TLR4 to SFK activation (Liu, et al., 2012). And finally, in MyD88-independent pathway, TICAM-1, an adapter molecule with a Pro- rich region and multiple potential isoform variants, mediates TLR4 signaling (Seya, et al., 2005).

Therefore, it seems reasonable to ask first, do proline-rich regions and/or motifs present in adapter-Accessory/scaffolding proteins of the opioid and Toll-Like 4 receptor signalling complexes on neurological and immunological cells bind similar proteins and could be one of the links between the immune and opioid systems? And second, is the internalization of adapter-Accessory/scaffolding receptor proteins, with domains or that binding proline-rich motifs/ regions, associate with opioid and TLR4 receptor signalling complexes, a mechanism for the regulation of the abundance of these interacting proteins?

References

Mace G, Jaume M, Blanpied C, Stephan L, Coudert JD, Druet P and Dietrich G (2002) Anti-opioid-receptor IgG antibodies are commonly present in serum from healthy blood donors: evidence for a role in apoptotic immune cell death. Blood 100(9):3261-8.

Need AC, Ge D, Weale ME, Maia J, Feng S, Heinzen EL, Shianna KV, Yoon W, Kasperavici?te D, Gennarelli M, Strittmatter WJ, Bonvicini C, Rossi G, Jayathilake K, Cola PA, McEvoy JP, Keefe RS, Fisher EM, St Jean PL, Giegling I, Hartmann AM, M?ller HJ, Ruppert A, Fraser G, Crombie C, Middleton LT, St Clair D, Roses AD, Muglia P, Francks C, Rujescu D, Meltzer HY, Goldstein D.B (2009) A genome-wide investigation of SNPs and CNVs in schizophrenia. PLoS Genet. 5, e1000373. doi:10.1371/journal.pgen.1000373.

Lozano R, Marin R, Freire I, Sebastian F, Santacruz MJ and Velilla A (2012) Schizophrenia: influence of single nucleotide polymorphisms on peptidic sequence. XXV Congress of Spanish Society of Clinical Pharmacology,(in press).

Talbot JN, Skifter DA, Bianchi E, Monaghan DT, Toews ML, and Murrin LC (2009) Regulation of mu opioid receptor internalization by the scaffold protein RanBPM. Neurosci Lett. 466(3): 154-158. doi:10.1016/j.neulet.2009.09.048.

Liu A, Gong P, Hyun SW, Wang KZ, Cates EA, Perkins D, Bannerman DD, Puch? AC, Toshchakov VY, Fang S, Auron PE, Vogel SN and Goldblum SE (2012) TRAF6 protein couples Toll-like receptor 4 signaling to Src family kinase activation and opening of paracellular pathway in human lung microvascular endothelia.. J Biol Chem. 287(20):16132-45.

Seya T, Oshiumi H, Sasai M, Akazawa T and Matsumoto M (2005) TICAM-1 and TICAM-2: toll-like receptor adapters that participate in induction of type 1 interferons. Int J Biochem Cell Biol 37(3):524-9.

Conflict of Interest:

None declared