Constitutive Desensitization of Opioid Receptors in Peripheral Sensory Neurons

Abstract

Opioid receptors expressed by peripheral pain-sensing neurons are functionally inactive for antinociceptive signaling under most basal conditions; however, tissue damage or exposure to inflammatory mediators (e.g., bradykinin) converts these receptors from a nonresponsive state to a functionally competent state. Here we tested the hypothesis that the basal, nonresponsive state of the mu-and delta-opioid receptors (MOR and DOR, respectively) is the result of constitutive receptor activity that activates desensitization mechanisms, resulting in MOR and DOR receptor systems that are constitutively desensitized. ]-enkephalin, inhibited prostaglandin E 2 (PGE 2 )-stimulated cAMP accumulation in peripheral sensory neurons in culture (ex vivo) or inhibited PGE 2 -stimulated thermal allodynia in the rat hind paw in vivo. Prolonged treatment with naloxone induced MOR and DOR responsiveness both in vivo and ex vivo to a similar magnitude as that produced by bradykinin. Also similar to bradykinin, the effect of naloxone persisted for 60 minutes after washout of the ligand. By contrast, prolonged treatment with 6b-naltrexol, did not induce functional competence of MOR or DOR but blocked the effect of naloxone. Treatment with siRNA for b-arrestin-2, but not b-arrestin-1, also induced MOR and DOR functional competence in cultured peripheral sensory neurons. These data suggest that the lack of responsiveness of MOR and DOR to agonist for antinociceptive signaling in peripheral sensory neurons is due to constitutive desensitization that is likely mediated by b-arrestin-2.

Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management

“…This long delay is not accounted for the by the rapid peak of 6BN levels reaching the circulation, but rather is consistent with gradual depletion of MOR-μ sites towards MOR-μ x sites. Similarly, the ability of 6BN, but not naltrexone, to reverse elevated MOR-μ* basal activity in chronic neuropathic pain is consistent with the model’s predictions [ 16 , 44 ].…”

“…Peripheral and central opioid receptor systems could interact dynamically, for example in the induction of opioid induced hyperalgesia, reported to be mediated both centrally and peripherally [ 14 , 15 ]. Peripheral MOR sites could have relevance to inflammation induced neuropathic pain, invoking beta-arestin-2 silenced MOR sites in afferent nociceptors [ 14 , 16 ], that get activated upon inflammatory stimuli. MOR activation could then suppress pain sensation, but also lead to a vicious circle of sustained neuropathic pain [ 14 , 16 ].…”

“…Peripheral MOR sites could have relevance to inflammation induced neuropathic pain, invoking beta-arestin-2 silenced MOR sites in afferent nociceptors [ 14 , 16 ], that get activated upon inflammatory stimuli. MOR activation could then suppress pain sensation, but also lead to a vicious circle of sustained neuropathic pain [ 14 , 16 ]. While an attractive model to account for the presence of ‘silent‘ MOR sites, the evidence is still missing how the activation occurs and whether these silent MOR sites perform signaling not measured by conventional means.…”

“…The possible presence of distinct MOR conformations, or varying relative abundance between conformations as a function of cellular environment, and in the periphery compared to the CNS, has been reviewed by Jeske [ 13 ], suggesting that beta-arrestin coupled MOR sites in afferent nociceptors account for their silent status, being activated only upon inflammatory stimuli. MOR-μ* basal activity appears also to be absent in peripheral afferent nociceptor neurons, but emerges upon nociceptive stimuli as a physiological countermeasure leading to abatement of neuropathic pain [ 16 , 44 ]. However, if such basal MOR activity fails to be reversed, it can contribute to chronic neuropathic pain.…”

“…However, if such basal MOR activity fails to be reversed, it can contribute to chronic neuropathic pain. Only 6BN, but not naltrexone, can facilitate the reversal of chronic neuropathic pain, revealing the biological relevance of MOR-μ* basal activity [ 16 , 44 ]. Whether such MOR sites also exist in the g.i.…”