GIRK channels have also been implicated in opioid tolerance and dependence due to adaptive changes in chronic exposure to morphine. However, opioid receptor agonist-induced desensitization of GIRK currents seems to involve additional mechanisms. In locus coeruleus neurons, inhibiting both G protein receptor kinase 2 (GRK2) and extracellular signal-regulated kinase (ERK) signaling significantly reduces the met-enkephalin induced GIRK channel desensitization that normally occurs within minutes of drug application142, an adrenergic nucleus in the pons that lowers pain threshold when activated. However, GIRK channel desensitization may not occur when μ-opioid receptors are activated by morphine. In fact, morphine elicits much less GIRK channel desensitization in vitro and in vivo143 compared to met-enkephalin. This response is surprising because met-enkephalin induces much less drug tolerance and dependence, than morphine. A recent report even suggests that the potency of morphine to reduce pain (i.e. the effect at a submaximal concentration) may actually increase during the development of tolerance (i.e. reduction of maximal effect) 144. This is paradoxical but could be explained if tolerance and dependence are mediated by effectors of opioid receptors other than GIRK channels.
