Functional compartmentalization of opioid desensitization in primary sensory neurons.

The cellular correlates of desensitization or tolerance are poorly understood. To address this, we studied acute and long-term mu-opioid desensitization, with respect to Ca(2+) currents, in cultured rat dorsal root ganglion (DRG) neurons. Exposure of DRG neurons to the mu-agonist [D-Ala(2),N-MePhe(4), Gly-ol(5)]-enkephalin (DAMGO; 3 microM) reduced whole-cell currents approximately 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 Ca(2+) channel regulation after washing and re-exposure to DAMGO. Responses to the gamma-aminobutyric acid(B) agonist baclofen were not affected in these neurons. Acute desensitization preferentially affected the voltage-sensitive component of mu-opioid and gamma-aminobutyric acid(B) responses. Facilitation of both the DAMGO- and baclofen-inhibited current by a strong depolarizing prepulse was significantly attenuated in acutely desensitized neurons. Because G(betagamma)-subunits mediate neurotransmitter-induced changes in channel voltage-dependent properties, these data suggest an altered interaction of the G(betagamma)-subunit with the Ca(2+) channel. Block of N-type Ca(2+) channels with omega-conotoxin GVIA revealed a component of the opioid response that did not desensitize over 10 min. We conclude that acute and long-term mu-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.