Abstract

Painful diabetic neuropathy is poorly controlled by analgesics and requires high doses of opioids, triggering side effects and reducing patient quality of life. This study investigated whether enhanced Rab7-mediated lysosomal targeting of peripheral sensory neuron μ-opioid receptors (MORs) is responsible for diminished opioid responsiveness in rats with streptozotocin-induced diabetes. In diabetic animals, significantly impaired peripheral opioid analgesia was associated with a loss in sensory neuron MOR and a reduction in functional MOR G-protein-coupling. In control animals, MORs were retained mainly on the neuronal cell membrane. In contrast, in diabetic rats, they were colocalized with upregulated Rab7 in LampI-positive perinuclear lysosome compartments. Silencing endogenous Rab7 with intrathecal Rab7-siRNA or, indirectly, by reversing nerve growth factor deprivation in peripheral sensory neurons not only prevented MOR targeting to lysosomes, restoring their plasma membrane density, but also rescued opioid responsiveness toward better pain relief. These findings elucidate in vivo the mechanisms by which enhanced Rab7 lysosomal targeting of MORs leads to a loss in opioid antinociception in diabetic neuropathic pain. This is in contrast to peripheral sensory neuron MOR upregulation and antinociception in inflammatory pain, and provides intriguing evidence that regulation of opioid responsiveness varies as a function of pain pathogenesis.

Abstract The contribution of supraspinal, spinal or peripheral mu-opioid receptors (MORs) to the overall antinociception of systemic centrally penetrating versus peripherally restricted opioids has not been thoroughly investi gated. Therefore, we examined paw pressure thresholds in Wistar rats with complete Freund’s adjuvant hindpaw inflammation following different doses of intraplantar (i.pl.) as well as intravenous (i.v.) fentanyl (6.25 50 mg/kg), morphine (1–7.5 mg/kg) or loperamide (1–7.5 mg/kg). Antago nism of the i.v. mu-opioid agonists by intracerebroventricular (i.c.v.), intrathecal (i.t.) or i.pl. naloxone-methiodide (NLXM) revealed the rela tive contributions of supraspinal, spinal and peripheral MOR to the overall antinociceptive effects. In parallel, the MOR density at these three levels of pain transmission was assessed by radioligand binding. Antinociceptive effects of i.v. fentanyl and morphine, but not of the peripherally restricted loperamide were two- to threefold greater and longer lasting compared with their i.pl. administration. I.c.v. but not i.pl. NLXM significantly antagonized fentanyl’s and morphine’s antinociception by 70–80%, whereas i.t. NLXM reduced it by 20–30%. In contrast, antinociception of i.v. loperamide was abolished by i.pl. but not by i.c.v. or i.t. NLXM. In parallel, a respective 32- and sixfold higher MOR density in supraspinal and spinal versus peripheral sensory neurons was detected. In conclusion, in comparison with supraspinal and spinal opioid receptors, peripheral opioid receptors do not significantly contribute to the antinociception of systemic fentanyl and morphine during inflammatory pain. Antinocicep tion of their i.v. administration was superior over both i.v and i.pl. lopera mide, acting exclusively via peripheral MOR. These findings may guide the future development of novel peripherally restricted opioids.

• Background and Aims: Loss in the antinociceptive efficacy of systemic, spinal, and supraspinal administration of opioids has been reported in rats with diabetic neuropathic pain. Recent studies investigated alterations in opioid receptor expression and signaling at the spinal level, however, results were conflicting. Since diabetic neuropathy is primarily a disease of the peripheral sensory neuron, this study aimed at investigating alterations of mu-opioid responsiveness during the development of streptozotocin-induced diabetic neuropathic pain in rats.

Background and Aims: The contribution of supraspinal, spinal or peripheral opioid receptors to the overall antinociceptive effects of centrally penetrating versus peripherally restricted opioids is still a matter of debate. Therefore, we examined the antinociceptive effects and its antagonism by intracerebroventricular, intrathecal or intraplantar naloxone methiodide of systemic fentanyl and morphine versus loperamide in relation to the density of mu-opioid receptors (MOR) at the three levels of pain transmission.

 Background and Aims: Painful diabetic neuropathy is a peripheral sensory neuron disease, is difficult to treat and is known to be less susceptible to opioid analgesics. In diabetic neuropathy little is known so far about alterations in mu-opioid receptor (MOR) expression, coupling and efficacy of sensory neurons within the spinal cord of diabetic neuropathy. Therefore, the aim of this study was to investigate the changes in MOR expression, signaling and function of sensory neurons at spinal cord level in streptozotocin induced diabetic rats. In addition, it is examined whether i.t. NGF treatment will restore the MOR expression and G-protein coupling and consequently will rescue the deficit in peripheral fentanyl induced analgesia of diabetic rats.

 Background and Aims: Visceral pain seems to be attenuated by intrathecal (i.t.) application of corticotropin-releasing factor (CRF) receptor antagonists. In contrast, i.t. CRF elicits inhibition of somatic pain that is reversed by the opioid antagonist naloxone. Previous studies have identified CRFR1 and more predominantly CRFR2 receptors within the dorsal horn of the spinal cord. At present it is unclear to which proportion each CRF receptor subtype contributes to the modulation of inflammatory somatic pain and on which opioid containing neuron population it is located.