Functional compartmentalization of opioid desensitization in primary sensory neurons

The cellular correlates of desensitization or tolerance are poorly understo od. To address this, we studied acute and long-term mu-opioid desensitizati on, with respect to Ca2+ currents, in cultured rat dorsal root ganglion (DR G) neurons. Exposure of DRG neurons to the mu-agonist [D-Ala(2),N-MePhe(4), Gly-ol(5)]-enkephalin (DAMGO; 3 mu M) reduced whole-cell currents similar t o 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 gamma-aminobutyric acid(B) agon ist baclofen were not affected in these neurons. Acute desensitization pref erentially affected the voltage-sensitive component of mu-opioid and gamma- aminobutyric acid(B) responses. Facilitation of both the DAMGO- and baclofe n-inhibited current by a strong depolarizing prepulse was significantly att enuated in acutely desensitized neurons. Because G(beta gamma)-subunits med iate neurotransmitter-induced changes in channel voltage-dependent properti es, these data suggest an altered interaction of the G(beta gamma)-subunit with the Ca2+ channel. Block of N-type Ca2+ channels with omega-conotoxin G VIA revealed a component of the opioid response that did not desensitize ov er 10 min. We conclude that acute and long-term mu-opioid desensitization i n DRG neurons occurs by different mechanisms. Acute desensitization is hete rologous and functionally compartmentalized: the pathway targeting non-N-ty pe channels is relatively resistant to the early effects of continuous agon ist exposure; the pathway targeting N-type channels in a largely voltage-in sensitive manner is partially desensitized; and the pathway targeting N-typ e channels in a largely voltage-sensitive manner is completely desensitized .