PubMed · 10069156
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N N Dubler. 1999. Commentary: promoting ethical flexibility.. https://doi.org/10.1016/s0885-3924(98)00138-9
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Globus pallidus receives, from dorsal neostriatum, a dense enkephalinergic innervation whose role is still uncertain. We examined the possibility that the activation of mu, delta or k opioid receptors modulate high-voltage-activated calcium currents in isolated GP neurons. Neither dynorphin nor DPEPE inhibited calcium current, whilst DAMGO produced a small (-16%) but consistent response, selectively antagonized by CTOP. The mu-mediated modulation required the activation of G-proteins but was voltage-independent. The pre-incubation in omega-conotoxinVIA abolished the response, implying the involvement of N-type calcium channels. These findings suggest that enkephalin may exert a direct influence on GP excitability also through post-synaptic effects. In degenerative conditions as Parkinsonism, an excessive stimulation of mu binding sites might induce a pathological inhibition of calcium signals, thus contributing to modify the GP firing pattern and transmitter release.
Traditional mechanisms thought to underlie opioid tolerance include receptor phosphorylation/down-regulation, G-protein uncoupling, and adenylyl cyclase superactivation. A parallel line of investigation also indicates that opioid tolerance development results from a switch from predominantly opioid receptor G(i alpha) inhibitory to G(beta gamma) stimulatory signaling. As described previously, this results, in part, from the increased relative abundance of G(beta gamma)-stimulated adenylyl cyclase isoforms as well as from a profound increase in their phosphorylation [Chakrabarti, S., Rivera, M., Yan, S.-Z., Tang, W.-J. & Gintzler, A. R. (1998) Mol. Pharmacol. 54, 655-662; Chakrabarti, S., Wang, L., Tang, W.-J. & Gintzler, A. R. (1998) Mol. Pharmacol. 54, 949--953]. The present study demonstrates that chronic morphine administration results in the concomitant phosphorylation of three key signaling proteins, G protein receptor kinase (GRK) 2/3, beta-arrestin, and G(beta), in the guinea pig longitudinal muscle myenteric plexus tissue. Augmented phosphorylation of all three proteins is evident in immunoprecipitate obtained by using either anti-GRK2/3 or G(beta) antibodies, but the phosphorylation increment is greater in immunoprecipitate obtained with G(beta) antibodies. Analyses of coimmunoprecipitated proteins indicate that phosphorylation of GRK2/3, beta-arrestin, and G(beta) has varying consequences on their ability to associate. As a result, increased availability of and signaling via G(beta gamma) could occur without compromising the membrane content (and presumably activity) of GRK2/3. Induction of the concomitant phosphorylation of multiple proteins in a multimolecular complex with attendant modulation of their association represents a novel mechanism for increasing G(beta gamma) signaling and opioid tolerance formation.