Involvement of the Nociceptin/Orphanin FQ-NOP receptor system in the ventrolateral periaqueductal gray following mechanical allodynia in chronic pain Giovanna M. Scoto a , Giuseppina Aricò a , Attilio Iemolo a , Simone Ronsisvalle b , Carmela Parenti a, ⁎ a Department of Pharmaceutical Sciences—Pharmacology Section, University of Catania, v.le A. Doria 6, 95125 Catania, Italy b Department of Pharmaceutical Sciences—Medicinal Chemistry, University of Catania, v.le A. Doria 6, 95125 Catania, Italy abstract article info Article history: Received 18 February 2009 Accepted 21 May 2009 Keywords: Neuropathy Inflammation Allodynia Nociceptin/Orphanin FQ Ventrolateral periaqueductal gray Descending pain modulation Aims: It has been well documented that ventrolateral periaqueductal gray (vlPAG) matter is a crucial component of the descending pain modulatory system in the chronic pain condition. The aim of the present study was to identify the role of the vlPAG Nociceptin/Orphanin FQ/NOP receptor system in allodynia, a nociceptive behavioral response associated with chronic pain. Main methods: We used two animal models of persistent pain: chronic constriction injury (CCI) and inflammation induced by carrageenan. In each, Nociceptin/Orphanin FQ transmission was abolished using UFP-101, a selective NOP receptor antagonist, which was injected into the vlPAG at a dose of 18 μg/1 μl/rat. Key findings: We found that treatment with the NOP antagonist reversed the decrease in allodynic threshold in CCI rats fourteen days after the ligature, which was the timepoint of the greatest reduction in threshold. Moreover, UFP-101 administered immediately prior to or 2 h after intra plantar (i.pl.) carrageenan injection prevented or reversed, respectively, allodynic behavior in rats with inflammation. Significance: Our findings support the hypothesis that the endogenous Nociceptin/Orphanin FQ/NOP receptor system is tonically active at the vlPAG level during neuropathic states or carrageenan inflammation. © 2009 Elsevier Inc. All rights reserved. Introduction Chronic pain is defined as a pain that persists longer than the temporal course of natural healing following a particular type of injury or disease process (Shipton and Tait 2005; Holden and Pizzi 2003). Chronic pain differs from acute pain by the duration of occurrence, threshold for stimulation and plastic alterations of the tissue (Dickenson 2008). Chronic pain is associated with significant altera- tions in sensory processing, such as hyperalgesia, which is an increased response to a stimulation that is normally painful, or allodynia, which results from a stimulus that does not normally provoke an algesic response (Schaible and Richter 2004; Dickenson 2008). Allodynia is the typical expression of chronic pain, and allodynic perception is selective for the sensory modality tested (thermal or mechanical stimulus) and the area examined (Riedel and Neeck 2001; Pertovaara et al. 1996). It is now well established that a significant contribution to the development and maintenance of mechanical allodynia arises from nociceptive perception processing in higher centers (Kovelowski et al. 2000). The periaqueductal gray matter (PAG) and the adjacent rostral ventromedial medulla (RVM), which includes projections to the spinal dorsal horns, constitute the efferent pathway of the pain-control system that descends from the brain to the spinal cord (Vanegas and Schaible 2004; Millan 2002). In particular, the ventrolateral columns of the PAG (vlPAG) are proposed to integrate behavioral nociceptive response (Odeh et al. 2003), and lidocaine injected into the vlPAG or the RVM has been demonstrated to attenuate tactile allodynia (Pertovaara et al. 1996). Nociceptin/Orphanin FQ (N/OFQ), a heptadecapeptide derived from preproN/OFQ (ppN/OFQ), is the endogenous ligand of the NOP receptor, which is widely distributed throughout the CNS in regions involved in pain transmission processing (Mogil and Pasternak 2001). Studies characterizing the role of N/OFQ in pain transmission have generated conflicting results depending on the dose of N/OFQ used and the site of administration (Civelli 2008). Supraspinal administration of the peptide has been shown to produce hyperalgesia, allodynia, and, in some circumstances, naloxone-reversible analgesia. In contrast, when admi- nistered intrathecally, N/OFQ has been shown to cause either allodynia or analgesia depending on the dose used (Rizzi et al. 2006). Immunohistochemical studies have shown a high density of NOP receptor localized in the PAG (Anton et al. 1996), where a high concentration of ppN/OFQ mRNA has also been found (Houtani et al. 1996). Microinjection of N/OFQ into the vlPAG was shown to decrease the withdrawal latency to heat and loading (Bytner et al. 2001). Moreover, we previously demonstrated that N/OFQ administered intra vlPAG (i.vlPAG) significantly diminished tail withdrawal latency to thermal stimulation, while UFP-101, the N/OFQ peptidic antagonist, Life Sciences 85 (2009) 206–210 ⁎ Corresponding author. Tel.: +39 095 7384025; fax: +39 095 7384213. E-mail addresses: scotog@unict.it (G.M. Scoto), garico@unict.it (G. Aricò), attilioiemolo@gmail.com (A. Iemolo), s.ronsisvalle@unict.it (S. Ronsisvalle), cparenti@unict.it (C. Parenti). 0024-3205/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2009.05.021 Contents lists available at ScienceDirect Life Sciences journal homepage: www.elsevier.com/locate/lifescie