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Cellular basis of itch sensation.
Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY, Chen ZF (2009) Cellular basis of itch sensation. Science 325:1531-1534. doi: 10.1126/science.1174868
Summary: Whether itch and pain use separate neuronal pathways has long been a subject of debate. The authors injected 400 ng of bombesin-SAP (Cat. #IT-40) into the intrathecal space of mice and examined itch and pain behavior. Lesioned mice had dramatic deficits in all itch behavior tested regardless of the histamine dependence of the itch. All pain behaviors, however, were left intact. These data indicate that the gastrin-releasing peptide receptor-expressing neurons are essential for itch transmission.
Related Products: Bombesin-SAP (Cat. #IT-40)
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)
Noradrenergic neurons in the locus coeruleus contribute to neuropathic pain.
Brightwell JJ, Taylor BK (2009) Noradrenergic neurons in the locus coeruleus contribute to neuropathic pain. Neuroscience 160:174-185. doi: 10.1016/j.neuroscience.2009.02.023
Summary: Noradrenergic neurons were eliminated with 5 µg intracerebroventricular injections of anti-DBH-SAP (Cat. #IT-03). Mouse IgG-SAP (Cat. #IT-18) was used as a control. Animals lesioned with anti-DBH-SAP displayed a reduction in behavioral signs of several kinds of allodynia.
Related Products: Anti-DBH-SAP (Cat. #IT-03), Mouse IgG-SAP (Cat. #IT-18)
Dependence of monocyte chemoattractant protein 1 induced hyperalgesia on the isolectin B4-binding protein versican.
Bogen O, Dina OA, Gear RW, Levine JD (2009) Dependence of monocyte chemoattractant protein 1 induced hyperalgesia on the isolectin B4-binding protein versican. Neuroscience 159:780-786. doi: 10.1016/j.neuroscience.2008.12.049
Summary: Monocyte chemoattractant protein 1 (MCP-1) is involved in generation of inflammatory and neuropathic pain, but the mechanisms underlying this involvement are not understood. Rats received 3.2 µg intrathecal injections of IB4-SAP (Cat. #IT-10). Ten days later the rats received intradermal MCP-1. Animals treated with IB4-SAP did not exhibit the mechanical hyperalgesia normally seen when treated with MCP-1.
Related Products: IB4-SAP (Cat. #IT-10)
Spinal NK-1 receptor-expressing neurons and descending pathways support fentanyl-induced pain hypersensitivity in a rat model of postoperative pain.
Rivat C, Vera-Portocarrero LP, Ibrahim MM, Mata HP, Stagg NJ, De Felice M, Porreca F, Malan TP (2009) Spinal NK-1 receptor-expressing neurons and descending pathways support fentanyl-induced pain hypersensitivity in a rat model of postoperative pain. Eur J Neurosci 29:727-737. doi: 10.1111/j.1460-9568.2009.06616.x
Summary: Opioids activate hyperalgesia and allodynia. The authors test the hypothesis that NK-1 receptor-containing ascending pathways play a role in sensitivity to fentanyl. Rats received an intrathecal injection of SP-SAP (Cat. #IT-07), and controls received saporin (Cat. #PR-01). The data indicate that these ascending pathways have a role in fentanyl-induced hyperalgesia.
Related Products: SP-SAP (Cat. #IT-07), Saporin (Cat. #PR-01)
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)
Lumbar intrathecal CCK-saporin: anatomic and nociceptive effects
Datta S, Chatterjee K, Kline IV RH, Wiley RG (2008) Lumbar intrathecal CCK-saporin: anatomic and nociceptive effects. Neuroscience 2008 Abstracts 773.4/MM32. Society for Neuroscience, Washington, DC.
Summary: Lumbar intrathecal CCK (cholecystokinin) appears anti-opiate in nocifensive reflex testing and may be important in opiate-resistant neuropathic pain states suggesting a role for CCK receptor-expressing dorsal horn neurons in nociception. In the present study, we sought to determine if selective destruction of CCK receptor-expressing superficial dorsal horn neurons alters pain sensitivity or the analgesic potency of morphine using the targeted cytotoxic conjugate (CCK-sap) of CCK to saporin, a ribosome inactivating protein. 28 adult Sprague Dawley rats were injected via lumbar intrathecal catheter with CCK-sap in doses of 500 ng (n=2), 350 ng (n=3), 700 ng (n=3), 1000 ng (n=4), 1500 ng (n=4), or 3000 ng (n=4). Controls included PBS (n=4) or 1500 ng of plain, unconjugated saporin (n=4). 2 weeks later rats were sacrificed. Lumbar spinal cords were frozen sectioned at 40 µm. One-in-six series of transverse sections at L4-6 were immunostained for CCK. Two rats were injected with 1500 ng of CCK-sap followed by transcardiac aldehyde perfusion in 72 hours. L5 Dorsal root ganglia (DRG) sections were stained with cresyl violet and examined for signs of acute cytotoxicity (chromatolysis and karyohexis). 350 to 1500 ng of intrathecal CCK-sap were well tolerated with no obvious signs of any toxicity. 3000 ng of intrathecal saporin led to motor signs within 72 hours including increased muscle tone, leading to tonic hind limbs extension. Subsequently, twelve Long Evans female rats were tested before and after intrathecal injection of either PBS (n=8) or CCK-sap, 1500 ng (n=4) on: 1 – cold plate (15 °C); 2 – thermal preference shuttle box testing (15/45°C); 3 – hotplate at 44°C, 47°C and 52°C and 4 – thermal preference after morphine (0.5, 1 and 2.5 mg/kg s.c). Anatomical analysis revealed that 1500 ng of CCK-sap decreased CCK immunostaining in the L4-6 Dorsal horn. No acute cytotoxicity was seen in the DRG with1500 ng CCK-sap. Intrathecal CCK-sap was well tolerated at doses ≤1500 ng. CCK-sap produced increased hot side time and decreased crossovers in the thermal preference test. In contrast, CCK-sap decreased latency to first hindpaw lift and increased total responding on the 44 °C hotplate. CCK-sap rats also showed increased hot side time at 45° C at all morphine doses (0, 1 and 2.5 mg/kg s.c.) also with decreased crossovers. We interpret these observations to indicate that CCK-sap produced increased nocifensive reflex responding on the 44° C hotplate consistent with positive modulation of motor responsiveness, and CCK-sap reduced aversion to 45° C heat consistent with an analgesic effect that was additive with morphine.
Related Products: CCK-SAP (Cat. #IT-31)
Contrasting effects of estrogen on memory tasks in young female rats
Saenz CM, Borowski T, De Lacalle S (2008) Contrasting effects of estrogen on memory tasks in young female rats. Neuroscience 2008 Abstracts 794.17/UU7. Society for Neuroscience, Washington, DC.
Summary: Sleep deprivation may lead to behavioral alterations and it has been associated with a hyperalgesic state in human beings and animal models. The tricyclic antidepressant amitriptyline can be used as an analgesic drug in patients and in chronic pain animal models that are not improved with classical analgesics, such as spinal nerve injury induced model of peripheral neuropathy. The pain hypersensitivity following both paradoxical sleep deprivation (PSD) and peripheral nerve injury shares common spinal mechanisms, which involve at least the glutamate receptors and nitric oxide. In this way, we evaluated the effects of amitriptyline pretreatment in the thermal hyperalgesia observed in paradoxical sleep deprived rats. Amitriptyline (10 and 30 mg/Kg) or saline were administered i.p. during 11 days to male Wistar rats (n = 7/group, 250 – 350 g). In the last 3 or 4 days of treatment the animals were submitted to 72 or 96 hours of PSD, respectively, or remained in home cages, being subsequently evaluated for their thermal sensitivity on a hot plate test (52oC or 46oC), 1 or 24 hours after the last drug administration. In order to verify if the results observed in the highest withdrawal latencies were due to a reduction on the locomotor activity rather than an analgesic effect, the number of squares crossed in an open field arena during 5 minutes, subsequently to the hot plate test was counted. The results demonstrated that paw withdrawal latency response to 52oC was significantly lower in paradoxical sleep deprived rats than controls (-37%, p<0.05). This hyperalgesic effect was also detected in animals pre-treated with 10 mg/kg (-41%, p<0.05) or 30 mg/Kg (-53%, p<0.05) of amitriptyline. At the highest dose, both groups presented a higher withdrawal threshold when compared to their respective saline groups (+185%, p<0.05 and +112%, p<0.05; control and sleep deprived rats, respectively). However, in the open field test a decrease in the number of squares crossed in control animals was observed (-52%, p<0.05), but not in sleep deprived rats (-3%, p>0.05). When the animals were allowed to recover for 24h from sleep deprivation, the pre-treatment with amitriptyline (10 mg/Kg) was not able to prevent the hyperalgesic state (-60%, p<0.05). Even with lower thermal stimulus (46oC) and sleep deprivation period (72h), the difference between control and sleep deprived animals could still be detected (-40%, p<0.05), with no changes after an amitriptyline 10 mg/Kg pre-treatment (-43%, p<0.05). Overall, these findings highlight that thermal pain hypersensitivity induced by PSD was not prevented by amitriptyline pre-treatment, as observed in other models of inductive pain.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Intra cisterna magna and Rostral ventromedial medulla injection of anti-Serotonin transporter-Saporinpertussis enhanced somatotopically different c-Fos expression and pain related behaviour in the medullary dorsal horn in rats
Sugiyo S, Uehashi D, Masawaki A, Ohyamaguchi A, Abe T, Yonehara N, Takemura M (2008) Intra cisterna magna and Rostral ventromedial medulla injection of anti-Serotonin transporter-Saporinpertussis enhanced somatotopically different c-Fos expression and pain related behaviour in the medullary dorsal horn in rats. Neuroscience 2008 Abstracts 369.11/KK23. Society for Neuroscience, Washington, DC.
Summary: The rostral ventromedial medulla (RVM) is a key center in descending pain modulator, which contain serotonergic neurons having descending projectional terminals in the trigeminal caudal nucleus (Vc; medullary dorsal horn). The functional significance of serotonergic neurons in the RVM is largely unknown. Pretreatment with anti IgG serotonin transporter conjugated with neurotoxin, saporin (anti-SERT-SAP; Advanced Targeting Systems) selectively eliminates cells bearing serotonin transporter, namely serotonergic neurons. 2-4 weeks after injection of anti-SERT-SAP (0.5 µM, 10 nl) into the RVM, the number of serotonin-immunoreactive (IR) cells in the RVM significantly decreased. Formalin injection (1,25% in saline) into the upper lip induced biphasic nociceptive pain-related behavior (PRB). In the rats anti-SERT-SAP-pretreated into the RVM, showed decreased the number of formalin-induced PRB at 1st and 2nd phase compared with the Blank-SAP-pretreated control. 2-4 weeks after intra cisterna magna (CM) pretreatment of anti-SERT-SAP(5 µM, 5 µl), the number of serotonin-IR cells in the RVM also reduced. In stark contrast to the results of pretreatment into the RVM, anti-SERT-SAP-pretreated rats into the CM increased the number of formalin-induced PRB at 1st and 2nd phase. These results indicate that serotonergic neurons in the RVM are constituted by two groups, 1) having pronociceptive function and 2) antinociceptive function projecting to the superficial layers of the Vc.
Related Products: Anti-SERT-SAP (Cat. #IT-23)