sb-334867-a and Facial-Pain

Involvement of the ventral tegmental area (VTA) and the lateral hypothalamus (LH) in the modulation of formalin-induced nociception is well documented. In this study, we investigated the role of orexin 1 (OX1) and orexin 2 (OX2) receptors within the VTA in modulation of the LH-induced antinociception during both phases of orofacial formalin test. Male adult Wistar rats weighing 230-250 g were unilaterally implanted with two stainless steel guide cannulae in the VTA and LH. In two separate supergroups, animals received SB334867 (OX1 receptor antagonist) or TCS OX2 29 (OX2 receptor antagonist), at the doses of 3, 10, and 30 nM/rat into the VTA before intra-LH microinjection of carbachol (250 nM/rat) as a nonselective cholinergic receptor agonist for chemical stimulation of orexinergic neurons in this region. Rats were subcutaneously injected with 1% formalin (50 µl; s) into the orofacial region, 5 min after intra-LH microinjection of carbachol or saline. The blockade of both orexin receptors in the VTA reduced intra-LH carbachol-induced antinociception. However, this effect was greater during the late phases of the orofacial formalin test. The blockade of the OX1 but not OX2 receptors in the VTA affect the pain-related behaviors during the early phase, and also, the contribution of OX2 receptor to modulate the LH-induced antinociceptive responses was greater than OX1 receptor during the late phase of orofacial formalin test. The results indicated the neural pathway projected from the LH to the VTA contributes to the modulation of formalin-induced orofacial pain. Orexinergic drugs might be considered as therapeutic agents for inflammatory pain treatment.

Topics: Animals; Benzoxazoles; Carbachol; Dose-Response Relationship, Drug; Facial Pain; Hypothalamic Area, Lateral; Isoquinolines; Male; Microinjections; Naphthyridines; Orexin Receptor Antagonists; Orexin Receptors; Pain Measurement; Pyridines; Rats; Urea; Ventral Tegmental Area

Lateral hypothalamus (LH) contains a large population of orexinergic neurons. Many studies have investigated the function of these neurons and it is clear that they are involved in pain modulation. The nucleus accumbens (NAc) receives many orexinergic projections, and accumbal neurons express both receptors of orexin (OX1R and OX2R). In this study, we investigated the role of accumbal orexinergic receptors in the LH-induced antinociception during formalin-induced orofacial pain. Male adult Wistar rats weighing 230-250 g were used in this study. Cannulae were unilaterally implanted in their skull for microinjections. SB334867 (OX1 receptor antagonist) or TCS OX2 29 (OX2 receptor antagonist) at the doses of 3, 10 and 30 nM were injected into the NAc with/without intra-LH microinjection of carbachol (250 nM/rat). Carbachol was used for chemical stimulation of orexinergic neurons in the LH. Our results showed that intra-LH carbachol following injection of formalin into animals' upper lip reduced nociception in both phases of formalin test. SB334867 and TCS OX2 29 were able to reduce LH-induced antinociception in both phases. Although the highest dose of SB334867 and TCS OX2 29 (30 nM) was effective in both phases, the TCS OX2 29 but not SB334867 at the dose of 10 nM could not reduce the antinociceptive responses induced by LH stimulation during the first (early) phase. It suggests that contribution of accumbal orexinergic receptors in the first phase of formalin test is more than the second (late) phase, and these results provide further evidence for the involvement of orexinergic system in the modulation of inflammatory orofacial pain.

Topics: Analgesics, Non-Narcotic; Animals; Benzoxazoles; Carbachol; Facial Pain; Formaldehyde; Hypothalamic Area, Lateral; Isoquinolines; Male; Naphthyridines; Nociception; Nucleus Accumbens; Orexin Receptor Antagonists; Orexin Receptors; Pyridines; Rats, Wistar; Urea

The role of hippocampus and lateral hypothalamus (LH) in modulation of formalin-induced nociception has been established. The present study aims to examine the role of orexin receptors in the Cornu Ammonis 1 (CA1) region of hippocampus in modulation of the LH-induced antinociception in the orofacial formalin test. Male Wistar rats were unilaterally implanted with two cannulae into the LH and CA1. Intra-LH microinjection of carbachol was done 5min after intra-CA1 administration of SB-334867 (OX1R antagonist) or TCS OX2 29 (OX2R antagonist). After 5min, 50μl of 1% formalin was subcutaneously injected into the upper lip for inducing the nociceptive behaviors. Solely intra-LH administration of carbachol reduced early and late phases of formalin-induced orofacial nociception in a dose-dependent manner. The antinociception evoked by intra-LH injection of carbachol (0.5μl of 250nM carbachol) was antagonized by intra-CA1 administration of 0.5μl of 3, 10 and 30nM solutions of SB-334867 or TCS OX2 29 during the early and late phases of orofacial formalin test. This effect was more remarkable during the late phase in comparison to the early phase. In addition, anti-analgesic effect of SB-334867 was more than TCS OX2 29 during the early and late phases. The results suggest the interpretation that a neural pathway from the LH to the CA1 probably contributes to the modulation of formalin-induced orofacial nociception through recruitment of both CA1 orexin receptors. Clinical studies are recommended to study the probable effectiveness of orexinergic system in modulation of the orofacial nociceptive responses.

Topics: Analgesics; Animals; Benzoxazoles; CA1 Region, Hippocampal; Facial Pain; Formaldehyde; Isoquinolines; Male; Naphthyridines; Orexin Receptor Antagonists; Orexin Receptors; Pyridines; Rats; Rats, Wistar; Urea

The neuropeptide orexin-A and its receptors are widely distributed in both hippocampal circuitry and pain transmission pathways. Involvement of the CA1 orexin 1 receptor (OX1R) on the modulation of orofacial pain and pain-induced changes in hippocampal expression of cyclooxygenase-2 (COX-2) and brain-derived neurotrophic factor (BDNF) was investigated.. Orofacial pain was induced by an intra-lip injection of capsaicin (100 μg). Reverse transcription polymerase chain reaction and immunoblot analysis were used to indicate changes in hippocampal BDNF and COX-2 expression, respectively.. Capsaicin induces a significant pain response, which is not affected by either orexin-A or SB-334867-A, an OX1R antagonist. However, an increased expression of COX-2 and decreased expression of BDNF was observed in the hippocampus of animals that received capsaicin or SB-334867-A (80 nM) plus capsaicin. Meanwhile, orexin-A (40 pM) attenuated the effects of capsaicin on the expression of COX-2 and BDNF.. CA1 OX1R activation moderates capsaicin-induced neuronal inflammation and neurotrophic deficiency.

Topics: Animals; Benzoxazoles; Brain-Derived Neurotrophic Factor; Capsaicin; Cyclooxygenase 2; Disease Models, Animal; Facial Pain; Hippocampus; Male; Naphthyridines; Neurons; Orexin Receptors; Orexins; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Urea

It is widely accepted that the spinal trigeminal nuclear complex, especially the subnucleus caudalis (Vc), receives input from orofacial structures. The neuropeptides orexin-A and -B are expressed in multiple neuronal systems. Orexin signaling has been implicated in pain-modulating system as well as learning and memory processes. Orexin 1 receptor (OX1R) has been reported in trigeminal nucleus caudalis. However, its roles in trigeminal pain modulation have not been elucidated so far. This study was designed to investigate the role of Vc OX1R in the modulation of orofacial pain as well as pain-induced learning and memory deficits. Orofacial pain was induced by subcutaneous injection of capsaicin in the right upper lip of the rats. OX1R agonist (orexin-A) and antagonist (SB-334867-A) were microinjected into Vc prior capsaicin administration. After recording nociceptive times, learning and memory was investigated using Morris water maze (MWM) test. The results indicated that, orexin-A (150 pM/rat) significantly reduced the nociceptive times, while SB334867-A (80 nM/rat) exaggerated nociceptive behavior in response to capsaicin injection. In MWM test, capsaicin-treated rats showed a significant learning and memory impairment. Moreover, SB-334867-A (80 nM/rat) significantly exaggerated learning and memory impairment in capsaicin-treated rats. However, administration of orexin-A (100 pM/rat) prevented learning and memory deficits. Taken together, these results indicate that Vc OX1R was at least in part involved in orofacial pain transmission and orexin-A has also a beneficial inhibitory effect on orofacial pain-induced deficits in abilities of spatial learning and memory.

Topics: Animals; Benzoxazoles; Capsaicin; Disease Models, Animal; Dose-Response Relationship, Drug; Facial Pain; Learning Disabilities; Male; Maze Learning; Memory Disorders; Motor Activity; Naphthyridines; Orexin Receptor Antagonists; Orexin Receptors; Orexins; Psychomotor Performance; Rats; Rats, Wistar; Reaction Time; Sensory System Agents; Spatial Learning; Trigeminal Nuclei; Urea

The relationship between anxiety and pain has received special attention. Orexins (A and B) are hypothalamic neuropeptides that have diverse functions in the regulation of different physiological and behavioral responses. This study was designed to evaluate the role of orexin 1 receptors (OX1R) within trigeminal nucleus caudalis (TNC) in anxiety following the induction of orofacial pain. The subcutaneous injection of capsaicin (CAP) into the rat upper lip region produced pain responses. OX1R agonist (orexin A) and antagonist (SB-334867) were microinjected into the TNC before the administration of CAP. Anxiety behaviors were investigated using elevated plus maze (EPM) and open-field tests. The results showed that CAP injection significantly decreases the percentage of time spent in the open arms of the EPM and the time spent in the center of the open field. Surprisingly, orexin (50, 100, and 150 pM/rat) significantly exaggerated the CAP effects, whereas SB-334867 (20, 40 nM/rat) significantly inhibited the CAP-induced anxiety. The CAP-injected group showed a significant decrease in the percentage of entries to open arms in the EPM and the number of visits in the center area of the open field compared with the control group. Orexin significantly potentiated the mentioned effects of CAP, whereas SB-334867 (40, 80 nM/rat) exerted a significant inhibitory effect on CAP-induced anxiety. The overall results indicated that the TNC OX1Rs play an important role in orofacial pain-induced anxiety.

Topics: Animals; Anxiety; Benzoxazoles; Capsaicin; Disease Models, Animal; Exploratory Behavior; Facial Pain; Formaldehyde; Male; Maze Learning; Microinjections; Naphthyridines; Orexin Receptor Antagonists; Orexin Receptors; Orexins; Pain Measurement; Rats; Rats, Wistar; Time Factors; Trigeminal Nuclei; Urea