A Cellular Mechanism for the Bidirectional Pain-Modulating Actions of Orphanin FQ/Nociceptin  Zhizhong Z. Pan, Naomi Hirakawa, Howard L. Fields  Neuron  Volume 26, Issue 2, Pages 515-522 (May 2000) DOI: 10.1016/S0896-6273(00)81183-6

Figure 1 OFQ/N-Produced Inhibition of NRM Cells (A) Outward currents induced by the κ receptor agonist U69593 and by OFQ/N in the same primary cell under voltage clamp (holding potential = −60 mV). (B) Outward currents produced by both OFQ/N and [met]enkephalin acting on the μ receptor (Pan et al. 1990) in a secondary cell. (C) A dose–response graph for the OFQ/N inhibition. Four data points (mean ± SE) from each of 7 cells of both types were pooled and fitted with the logistic equation. Neuron 2000 26, 515-522DOI: (10.1016/S0896-6273(00)81183-6)

Figure 2 OFQ/N-Induced Increase of an Inwardly Rectifying Potassium Conductance (A) A current–voltage plot in the absence (open circle) and presence (closed circle) of OFQ/N (100 nM) in two extracellular potassium concentrations. Arrows indicate reversal potentials. (B) Subtracted currents induced by OFQ/N from (A). Note the inward rectification. Neuron 2000 26, 515-522DOI: (10.1016/S0896-6273(00)81183-6)

Figure 3 Occlusion of OFQ/N- and κ or μ Receptor–Mediated Inhibitions in NRM Cells (A) (Upper panel) Recording of membrane potential in a κ-sensitive primary cell under current clamp. In the presence of OFQ/N (300 nM), addition of the κ agonist U69593 (300 nM) caused no further hyperpolarization. (Lower panel) A histogram summarizing data from a group of primary cells (n = 8) under voltage clamp. There is no significant difference between outward currents induced by OFQ/N alone and by OFQ/N plus U69593 (p > 0.05, Student's t test). (B) (Upper panel) Recording of membrane potential under current clamp in a μ-sensitive secondary cell. Spontaneous action potentials are truncated. On top of the OFQ/N (300 nM)-induced hyperpolarization, the μ agonist DAMGO (1 μM) produced no further inhibition. (Lower panel) A histogram showing group data in secondary cells (n = 9). The outward current induced by OFQ/N plus DAMGO is not significantly different from that by OFQ/N alone (p > 0.05, Student's t test). Neuron 2000 26, 515-522DOI: (10.1016/S0896-6273(00)81183-6)

Figure 4 Antianalgesic Effect of OFQ/N in the NRM Tail flick latencies (mean ± SE) were measured before (BL for baseline, averages of six trials) and after drug microinjections (arrow) in six groups of rats (n = 5 or 6 rats in each group). (A) Open circle, DAMGO in the PAG and saline in the NRM; closed circle, DAMGO in the PAG and OFQ/N in the NRM; open square, DAMGO in the PAG and OFQ/N + norBNI in the NRM; closed square, saline in the PAG and OFQ/N in the NRM; (B) closed triangle, DAMGO in the PAG and OFQ/N outside the NRM; open diamond, DAMGO in the PAG and CTOP in the NRM; and closed square, from (A). Asterisks denote data points in the group (closed circle) that are statistically different from those in the group (open circle) (*, p < 0.05; **, p < 0.01; ANOVA and post hoc analysis). Neuron 2000 26, 515-522DOI: (10.1016/S0896-6273(00)81183-6)

Figure 5 Antihyperalgesic Effect of OFQ/N in the NRM Morphine injection (i.v.) was followed by naloxone (i.v.) 26 min later (arrowheads) and then by NRM microinjection (arrow) of either OFQ/N (closed circle, n = 7 rats) or saline (open circle, n = 7) 14 min after naloxone injection (*, p < 0.05; **, p < 0.01; ANOVA and post hoc analysis). Neuron 2000 26, 515-522DOI: (10.1016/S0896-6273(00)81183-6)

Figure 6 Schematic Illustration of the Mechanisms for the Bidirectional Pain-Modulating Actions of OFQ/N in the NRM OFQ/N receptors (O/N) are located in both μ-sensitive secondary cells and κ-sensitive primary cells. Analgesic opioids acting on μ receptors inhibit the secondary cell and disinhibit the primary cell whose activation produces analgesia. OFQ/N inhibits the analgesia through its inhibitory action predominantly on the activated primary cell during opioid analgesia. Activation of the secondary cell contributes to the hyperalgesia during opioid withdrawal. OFQ/N antagonizes the hyperalgesia by inhibiting the relatively active secondary cell during opioid withdrawal. Presumably, primary cells receive a GABA-ergic input from a subset of secondary cells. Neuron 2000 26, 515-522DOI: (10.1016/S0896-6273(00)81183-6)