Nociceptin/orphanin FQ receptor modulates painful and fatigue symptoms in a mouse model of fibromyalgia.

Generalized pain and fatigue are both hallmarks of fibromyalgia, a syndrome with an indefinite aetiology. The treatment options for fibromyalgia are currently limited, probably due to its intricate pathophysiology. Thus, further basic and clinical research on this condition is currently needed. This study investigated the effects of nociceptin/orphanin FQ (N/OFQ) receptor (NOPr) ligands and the modulation of the NOP system in the preclinical mouse model of reserpine-induced fibromyalgia. The effects of administration of the natural agonist N/OFQ and the selective NOPr antagonists (UFP-101 and SB-612111) were evaluated in fibromyalgia-related symptoms in reserpine-treated mice. The expression of preproN/OFQ (ppN/OFQ) and NOPr was assessed in central and peripheral sites at different time-points after reserpine administration. N/OFQ displayed dual effects in the behavioural changes in the reserpine-elicited fibromyalgia model. The peptide NOPr antagonist UFP-101 produced analgesic and anti-fatigue effects, by preventing alterations of brain activity and skeletal muscle metabolism, secondary to fibromyalgia induction. The non-peptide NOPr antagonist SB-612111 mirrored the favourable effects of UFP-101 in painful and fatigue alterations induced by reserpine. A time-related up- or down-regulation of ppN/OFQ and NOPr was observed in supraspinal, spinal and peripheral sites of reserpine-treated mice. Our data shed new lights on the mechanisms underlying the fibromyalgia pathogenesis, supporting a role for N/OFQ-NOP receptor system in this syndrome.