Nitric oxide modulates μ‐opioid receptor function in vitro

Painful diabetic neuropathy (PDN) is a type of peripheral neuropathic pain that develops as a consequence of prolonged hyperglycaemia‐induced injury to the long nerves. Apart from pain, PDN is also characterized by morphine hyposensitivity. Intriguingly, in streptozotocin (STZ)‐induced diabetic rats exhibiting marked morphine hyposensitivity, dietary administration of the nitric oxide (NO) precursor, L‐arginine at 1 g/d, progressively rescued morphine efficacy and potency over an 8‐week treatment period. In earlier work, single bolus doses of the furoxan nitric oxide (NO) donor, PRG150 (3‐methylfuroxan‐4‐carbaldehyde), evoked dose‐dependent pain relief in STZ‐diabetic rats but the efficacious doses were 3‐4 orders of magnitude higher in advanced diabetes than that required in early STZ diabetes. Together, these findings suggested a role for NO in the modulation of μ‐opioid (MOP) receptor signalling. Therefore, the present study was designed to assess a role for NO released from PRG150, in modulating MOP receptor function in vitro. Here, we show an absolute requirement for the MOP receptor, but not the δ‐opioid (DOP) or the κ‐opioid (KOP) receptor, to transduce the cellular effects of PRG150 on forskolin‐stimulated cAMP responses in vitro. PRG150 did not interact with the classical naloxone‐sensitive binding site of the MOP receptor, and its effects on cAMP responses in HEK‐MOP cells were also naloxone‐insensitive. Nevertheless, the inhibitory effects of PRG150 on forskolin‐stimulated cAMP responses in HEK‐MOP cells were dependent upon pertussis toxin (PTX)‐sensitive Gi/o proteins as well as membrane lipid rafts and src kinase. Together, our findings implicate a role for NO in modulating MOP receptor function in vivo.

• Publication year

  2019

• Venue

  Clinical and Experimental Pharmacology and Physiology

• Publication date

  2019-07-01

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1111/1440-1681.13091PMID 30933370
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• 1 Supplementary Material

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