@article {Samoriski500, author = {Gary M. Samoriski and Robert A. Gross}, title = {Functional Compartmentalization of Opioid Desensitization in Primary Sensory Neurons}, volume = {294}, number = {2}, pages = {500--509}, year = {2000}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {The cellular correlates of desensitization or tolerance are poorly understood. To address this, we studied acute and long-term μ-opioid desensitization, with respect to Ca2+ currents, in cultured rat dorsal root ganglion (DRG) neurons. Exposure of DRG neurons to the μ-agonist [d-Ala2,N-MePhe4,Gly-ol5]-enkephalin (DAMGO; 3 μM) reduced whole-cell currents \~{}35\%, but with continued agonist application, 52\% of the response was lost over 10 to 12 min. In contrast, exposure of DRG neurons to DAMGO for 24 h resulted in a nearly complete loss of Ca2+ channel regulation after washing and re-exposure to DAMGO. Responses to the γ-aminobutyric acidB agonist baclofen were not affected in these neurons. Acute desensitization preferentially affected the voltage-sensitive component of μ-opioid and γ-aminobutyric acidB responses. Facilitation of both the DAMGO- and baclofen-inhibited current by a strong depolarizing prepulse was significantly attenuated in acutely desensitized neurons. Because Gβγ-subunits mediate neurotransmitter-induced changes in channel voltage-dependent properties, these data suggest an altered interaction of the Gβγ-subunit with the Ca2+channel. Block of N-type Ca2+ channels with ω-conotoxin GVIA revealed a component of the opioid response that did not desensitize over 10 min. We conclude that acute and long-term μ-opioid desensitization in DRG neurons occurs by different mechanisms. Acute desensitization is heterologous and functionally compartmentalized: the pathway targeting non-N-type channels is relatively resistant to the early effects of continuous agonist exposure; the pathway targeting N-type channels in a largely voltage-insensitive manner is partially desensitized; and the pathway targeting N-type channels in a largely voltage-sensitive manner is completely desensitized. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/294/2/500}, eprint = {https://jpet.aspetjournals.org/content/294/2/500.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }