Nociceptin Levels in the Cerebrospinal Fluid of Chronic Pain Patients With or Without Intrathecal Administration of Morphine

Abstract

The neuropeptide nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the opioid-like receptor ORL-1 and is thought to be involved in pain transmission and modulation. Human studies have not yet defined its role in pain patients. The aims of this study were 1) to verify the presence of N/OFQ in the cerebrospinal fluid (CSF) of human controls and patients with chronic noncancer pain, including those treated with intrathecally administered morphine, and 2) to determine whether pain or treatment with long-term intrathecal morphine influences its levels. The CSF of 27 patients (nine controls and 18 with chronic noncancer pain, of whom 12 were treated chronically with intrathecally administered morphine and six were opioid naïve) was analyzed, blindly, with radioimmunoassay methods. N/OFQ was detected in all patients. Mean CSF concentrations were lowest in the morphine-treated group and highest in the untreated chronic pain patients (12.06+/-1.19 and 57.41+/-10.06 fmol/ml, respectively), and the difference between the morphine-treated group and controls was statistically significant (44.72+/-13.56 fmol/ml, P<0.05). The presence of N/OFQ peptide in human CSF may correlate with biological activities that are influenced by different pain states and long-term intrathecal-morphine treatment. Further studies should verify whether the determination of this peptide CSF level may provide information on opioid treatment efficacy and on the presence of opioid tolerance.

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

“…Furthermore, SR16835, which is inactive in blocking tail flick acute pain, was able to attenuate SNL-induced mechanical allodynia, an action also blocked by SB-612111 (Khroyan et al, 2011). These results are consistent with chronic pain-, as well as chronic inflammation-induced changes in the levels of NOP receptor mRNA, N/OFQ peptide levels, and ppN/OFQ mRNA levels in rodents (Andoh et al, 1997;Itoh et al, 2001;Briscini et al, 2002;Witta et al, 2003) and humans (Raffaeli et al, 2006) and once again suggest that NOP agonists might have better success in treatment of chronic or inflammatory rather than nociceptive acute pain.…”

Differential Effects of Nociceptin/Orphanin FQ (NOP) Receptor Agonists in Acute versus Chronic Pain: Studies with Bifunctional NOP/μ Receptor Agonists in the Sciatic Nerve Ligation Chronic Pain Model in Mice

“…A significant increase in brain N/OFQ immunoreactivity has also been demonstrated in SNL rats (Sun et al, 2001), as well as an increase in NOP receptors in superficial laminae of the rat spinal cord subsequent to CFA injection, as determined by in vitro autoradiography (Jia et al, 1998). Furthermore, increased levels of N/OFQ have been reported in the cerebrospinal fluid of patients with chronic pain (Raffaeli et al, 2006). These studies suggest that exogenously applied NOP agonists and/or antagonists may have activity in chronic pain animals.…”

Sex differences in the Nociceptin/Orphanin FQ system in rat spinal cord following chronic morphine treatment

“…Indeed, a recent clinical study found higher levels of N/OFQ in the CSF of chronic pain patients compared to controls. In that study, N/OFQ levels were reduced over 75% in chronic pain patients (mainly males) who received prolonged intrathecal morphine compared to male and female patients receiving no morphine (Raffaeli et al, 2006). …”