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Evaluation of side effects through selective ablation of the mu opioid receptor expressing descending nociceptive facilitatory neurons in the rostral ventromedial medulla with dermorphin-saporin.
Cao F, Chen SS, Yan XF, Xiao XP, Liu XJ, Yang SB, Xu AJ, Gao F, Yang H, Chen ZJ, Tian YK (2009) Evaluation of side effects through selective ablation of the mu opioid receptor expressing descending nociceptive facilitatory neurons in the rostral ventromedial medulla with dermorphin-saporin. Neurotoxicology 30(6):1096-1106. doi: 10.1016/j.neuro.2009.06.004
Summary: Selective ablation of rostral ventromedial (RVM) neurons expressing mu opioid receptors has been suggested as a treatment for pathological pain. This work investigated the side effects of a 0.5 µg injection of dermorphin-SAP (Cat. #IT-12) into the RVM. Saporin (Cat. #PR-01) was used as a control. Lesioned animals experienced a temporary increase in heart rate and systolic blood pressure, and mild microglial responses, but even these soon returned to normal. The data suggest this system has potential as a target for pain therapeutics.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12), Saporin (Cat. #PR-01)
Sex differences in micro-opioid receptor expression in the rat midbrain periaqueductal gray are essential for eliciting sex differences in morphine analgesia.
Loyd DR, Wang X, Murphy AZ (2008) Sex differences in micro-opioid receptor expression in the rat midbrain periaqueductal gray are essential for eliciting sex differences in morphine analgesia. J Neurosci 28:14007-14017. doi: 10.1523/JNEUROSCI.4123-08.2008
Summary: The authors test whether the periaqueductal gray (PAG), that contains a dense population of µ-opioid receptor (MOR)-expressing neurons, is sexually dimorphic. Rats were injected with 3 pmol of Dermorphin-SAP (Cat. #IT-12) into the PAG. Blank-SAP (Cat. #IT-21) was used as a control. Both behavioral and immunohistochemical evidence suggest that differential expression of MOR-expressing neurons in the PAG between male and female rats accounts for the difference in response to morphine.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12), Blank-SAP (Cat. #IT-21)
Neuropathic pain is maintained by brainstem neurons co-expressing opioid and cholecystokinin receptors.
Zhang W, Gardell S, Zhang D, Xie JY, Agnes RS, Badghisi H, Hruby VJ, Rance N, Ossipov MH, Vanderah TW, Porreca F, Lai J (2009) Neuropathic pain is maintained by brainstem neurons co-expressing opioid and cholecystokinin receptors. Brain 132:778-787. doi: 10.1093/brain/awn330
Summary: It has been hypothesized that a subset of rostral ventromedial medulla (RVM) neurons co-expressing the cholecystokinin type 2 receptor and the mu-opioid receptor are responsible for the maintenance of neuropathic pain. Rats were treated with 50-ng bilateral RVM injections of Dermorphin-SAP (Cat. #IT-12), CCK-SAP (Cat. #IT-31), or saporin (Cat. #PR-01) as a control. Lesion of the RVM neurons prevented hyperalgesia in response to CCK treatment, and shortened abnormal pain states caused by sciatic nerve injury.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12), CCK-SAP (Cat. #IT-31), Saporin (Cat. #PR-01)
Analysis of inhibitory phase of formalin test: Effects of specific neural lesions
Wiley RG, Moore SA, Kline IV RH (2008) Analysis of inhibitory phase of formalin test: Effects of specific neural lesions. Neuroscience 2008 Abstracts 772.4/MM19. Society for Neuroscience, Washington, DC.
Summary: The formalin test has been widely used as a model of persistent pain. The 90 mins of formalin-induced nocifensive responding can be divided into two phases (phase 1, first ~10 mins; phase 2, last ~60 mins) separated by a period of reduced responding (interphase, IP), that has received relatively little attention. Behavioral inhibition during the IP of the formalin test has been associated with electrophysiological evidence of inhibition of dorsal horn nociceptive neurons (Henry et al, Pain, 82:57, 1999), probably due, at least in part, to local spinal mechanisms. Behavioral inhibition during IP has been shown to be enhanced by morphine and suppressed by naloxone. In the present study, we sought to determine the effect of selective depletion of specific dorsal horn interneurons known to be involved in nociception, i.e. neurons expressing NPY1R, GalR1 or MOR, or selective destruction of cerebral noradrenergic neurons or spinal cord projecting 5-HT neurons on formalin-induced nociceptive behavior, with particular attention to IP. Type-selective lesions were produced by lumbar intrathecal injection of NPY-saporin, galanin-saporin or dermorphin-saporin, respectively. Cerebral noradrenergic neurons and spinally projecting 5-HT neurons were destroyed using the immunotoxins, anti-DBH-saporin (intracerebroventricular) or anti-SERT-saporin (lumbar intrathecal), respectively. Partial loss of dorsal horn interneurons expressing NPY1R or GalR1 decreased nocifensive responding during IP and phase 2 of the formalin test, while partial loss of MOR-expressing dorsal horn interneurons increased nocifensive responding during IP and during phase 2. Both antiDBH-sap and antiSERT-sap decreased responding during IP, without effects on either phase 1 or 2. These results suggest that the apparent anti-nociception during IP and phase 2 produced by loss of NPY1R- and GalR1-expressing dorsal horn neurons is due to increased inhibition over excitation/facilitation of nociceptive projection neurons, whereas depletion of MOR-expressing interneurons produces the opposite effect. The apparent enhanced nociception during IP, but not phase I and II, produced by anti-DBH-sap and anti-SERT-sap suggests that these neural systems serve to enhance the excitability of nociceptive projection neurons during the formalin IP. Electrophysiologic and pharmacologic studies of formalin IP in selectively lesioned animals combined with the above behavioral findings may reveal new insights into endogenous modulation of nocifensive motor responses and/or nociception.
Related Products: NPY-SAP (Cat. #IT-28), Anti-SERT-SAP (Cat. #IT-23), Galanin-SAP (Cat. #IT-34), Anti-DBH-SAP (Cat. #IT-03), Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
Lumbosacral-bulbo-spinal loop relayed by RVM on-cells regulates visceral nociception and modulates inhibitory effects of pregabalin and ondansetron
Sikandar S, Dickenson AH (2008) Lumbosacral-bulbo-spinal loop relayed by RVM on-cells regulates visceral nociception and modulates inhibitory effects of pregabalin and ondansetron. Neuroscience 2008 Abstracts 269.4/GG19. Society for Neuroscience, Washington, DC.
Summary: Descending controls from brainstem nuclei including the rostral ventromedial medulla (RVM) have been shown to play an important role in visceral pain, and compounds modulating serotonergic receptor activity and compounds targeting the α2δ subunit of voltage-gated calcium channels have demonstrated clinical efficacy in providing symptomatic relief in patients with visceral hyperalgesia. We investigated the role of RVM on-cells and a serotonergic lumbosacral-bulbo-spinal loop in visceral hyperalgesia and examined the antihyperalgesic effects of ondansetron and pregabalin in modifying visceral pain responses to colorectal distension (CRD) in rats. An in vivo model of visceral pain was established involving CRD and a reliable EMG recording protocol for measuring activity in the external oblique muscle following CRD for quantifying evoked visceromotor responses (VMR) in Sprague-Dawley rats. Changes in VMR evoked by CRD in a range of 10-80 mmHg were recorded following administration of ondansetron (50 μg/kg i.t.) and pregabalin (30 mg/kg s.c.) in naïve rats and rats pretreated with 0.25% intracolonic mustard oil (MO) to induce colonic hyperalgesia. Moreover, RVM on-cells were selectively ablated with injection of the neurotoxin saporin conjugated to the μ-receptor agonist dermorphin (DermSAP) using stereotaxic techniques. Twenty-eight days post-injection, the VMR were compared between naïve, SAP and Derm-SAP rats in control conditions and following intracolonic MO. CRD produced graded VMR responses that were facilitated by intracolonic MO. Both ondansetron and pregabalin were shown to effectively reduce evoked VMR to CRD in naïve rats and MO pretreated rats by antagonizing spinal 5-HT3 receptors and by binding to the α2δ subunit of voltage-gated calcium channels, respectively. Moreover, DermSAP pretreatment was shown to reduce overall evoked VMR, and the antihyperalgesic efficacies of ondansetron and pregabalin were also shown to be modified by the loss of on-cells in DermSAP rats. Furthermore, we verified immunohistochemically RVM on-cell ablation in DermSAP rats and quantified RVM 5-HT cell intensity between naïve, SAP and DermSAP rats. This study illustrates the role of 5-HT3-mediated descending facilitatory controls in visceral pain as well as providing evidence for the antihyperalgesic efficacy of the second generation α2δ ligand pregabalin in the CRD model. Moreover, evidence is provided for a facilitatory serotonergic lumbosacral-bulbo-spinal loop relayed by RVM on-cells that is evoked by CRD and modulates efficacies of pregabalin and ondansetron.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
Descending facilitation from the brainstem determines behavioural and neuronal hypersensitivity following nerve injury and efficacy of pregabalin.
Bee LA, Dickenson AH (2008) Descending facilitation from the brainstem determines behavioural and neuronal hypersensitivity following nerve injury and efficacy of pregabalin. Pain 140:209-223. doi: 10.1016/j.pain.2008.08.008
Summary: Rostral ventromedial medulla (RVM) facilitatory On cells are thought to be involved in the mechanisms that control chronic pain. Dermorphin-SAP (Cat. #IT-12, 3 pmol injected into the RVM of rats) was used to examine how mu-opioid receptor expressing facilitatory cells fit into this circuit. Saporin (Cat. #PR-01) was used as a control. The results show that activity in the RVM may influence the outcome of nerve injury.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12), Saporin (Cat. #PR-01)
Featured Article: Selective lesions of amygdala intercalated neurons using the Dermorphin-SAP immunotoxin reveal their role in conditioned fear
Likhtik E (2008) Featured Article: Selective lesions of amygdala intercalated neurons using the Dermorphin-SAP immunotoxin reveal their role in conditioned fear. Targeting Trends 9(4)
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12), Blank-SAP (Cat. #IT-21)
Read the featured article in Targeting Trends.
See Also:
Amygdala intercalated neurons are required for expression of fear extinction.
Likhtik E, Popa D, Apergis-Schoute J, Fidacaro GA, Pare D (2008) Amygdala intercalated neurons are required for expression of fear extinction. Nature 454(7204):642-645. doi: 10.1038/nature07167
Summary: Scientists have been using fear learning in animals to study human anxiety disorders. In order to investigate the contribution of amygdala plasticity to fear learning, rats received 0.25-µl bilateral infusions of 3-µM dermorphin-SAP (Cat. #IT-12) into the amygdala. Blank-SAP (Cat. #IT-21) was used as a control. Lesioned rats displayed extinction expression deficits, indicating that the eliminated intercalated amygdala neurons play a large role in the extinction process.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12), Blank-SAP (Cat. #IT-21)
Spinal mu-opioid receptor-expressing dorsal horn neurons: role in nociception and morphine antinociception.
Kline IV RH, Wiley RG (2008) Spinal mu-opioid receptor-expressing dorsal horn neurons: role in nociception and morphine antinociception. J Neurosci 28:904-913. doi: 10.1523/JNEUROSCI.4452-07.2008
Summary: The authors used Dermorphin-SAP (Cat. #IT-12) to investigate the function of spinal cord mu-opioid receptor (MOR)-expressing dorsal horn neurons in nociception and morphine analgesia. Rats were treated with 500 ng intrathecal injections of Dermorphin-SAP; 500 ng of Blank-SAP (Cat. #IT-21), and up to 1 µg of Saporin (Cat. #PR-01) were used as controls. The data indicate that MOR-expressing dorsal horn neurons are necessary for morphine action and play a role in nocifensive responses to persistent pain in the formalin test.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12), Blank-SAP (Cat. #IT-21), Saporin (Cat. #PR-01)
Selective ablation of GABA neurons in the ventral tegmental area increases spontaneous locomotor activity.
Shank EJ, Seitz PK, Bubar MJ, Stutz SJ, Cunningham KA (2007) Selective ablation of GABA neurons in the ventral tegmental area increases spontaneous locomotor activity. Behav Neurosci 121:1224-1233. doi: 10.1037/0735-7044.121.6.1224
Summary: To further examine the importance of the ventral tegmental area (VTA) g-aminobutyric acid (GABA) neurons in behavioral function, the authors lesioned the VTA of rats with dermorphin-saporin (Cat. #IT-12). Lesioned animals received 1 or 2 pmol/200 nl bilateral injections of conjugate; blank-SAP (Cat. #IT-21) was used as a control. Rats treated with dermorphin-SAP displayed significantly elevated motility as compared to control animals. Rats receiving 1 pmol of dermorphin-SAP returned to normal motility 14 days after treatment, but rats receiving 2 pmol maintained the increased motility through day 14.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12), Blank-SAP (Cat. #IT-21)