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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypocretin (orexin) is synthesized by neurons in the lateral hypothalamus and has been reported to increase food intake and regulate the neuroendocrine system. In the present paper, long descending axonal projections that contain hypocretin were found that innervate all levels of the spinal cord from cervical to sacral segments, as studied in mouse, rat, and human spinal cord and not previously described. High densities of axonal innervation are found in regions of the spinal cord related to modulation of sensation and pain, notably in the marginal zone (lamina 1). Innervation of the intermediolateral column and lamina 10 as well as strong innervation of the caudal region of the sacral cord suggest that hypocretin may participate in the regulation of both the sympathetic and parasympathetic parts of the autonomic nervous system. Double-labeling experiments in mice combining retrograde transport of diamidino yellow after spinal cord injections and immunocytochemistry support the concept that hypocretin-immunoreactive fibers in the cord originate from the neurons in the lateral hypothalamus. Digital-imaging physiological studies with fura-2 detected a rise in intracellular calcium in response to hypocretin in cultured rat spinal cord neurons, indicating that spinal cord neurons express hypocretin-responsive receptors. A greater number of cervical cord neurons responded to hypocretin than another hypothalamo-spinal neuropeptide, oxytocin. These data suggest that in addition to possible roles in feeding and endocrine regulation, the descending hypocretin fiber system may play a role in modulation of sensory input, particularly in regions of the cord related to pain perception and autonomic tone.
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PMID:Hypothalamic hypocretin (orexin): robust innervation of the spinal cord. 1019 30

The hypothalamic peptide orexin-A and the orexin-1 receptor are localized in areas of the brain and spinal cord associated with nociceptive processing. In the present study, localization was confirmed in the spinal cord and demonstrated in the dorsal root ganglion for both orexin-A and the orexin-1 receptor. The link with nociception was extended when orexin-A was shown to be analgesic when given i.v. but not s.c. in mouse and rat models of nociception and hyperalgesia. The efficacy of orexin-A was similar to that of morphine in the 50 degrees C hotplate test and the carrageenan-induced thermal hyperalgesia test. However, involvement of the opiate system in these effects was ruled out as they were blocked by the orexin-1 receptor antagonist SB-334867 but not naloxone. Orexin-1 receptor antagonists had no effect in acute nociceptive tests but under particular inflammatory conditions were pro-hyperalgesic, suggesting a tonic inhibitory orexin drive in these circumstances. These data demonstrate that the orexinergic system has a potential role in the modulation of nociceptive transmission.
Pain 2001 May
PMID:Orexin-A, an hypothalamic peptide with analgesic properties. 1132 29

The hypothalamic peptides hypocretin-1 (orexin A) and hypocretin-2 (Hcrt-2; orexin B) are important in modulating behaviours demanding arousal, including sleep and appetite. Fibres containing hypocretin project from the hypothalamus to the superficial dorsal horn (SDH) of the spinal cord (laminae I and II); however, the effects produced by hypocretins on SDH neurones are unknown. To study the action of Hcrt-2 on individual SDH neurones, tight-seal, whole-cell recordings were made with biocytin-filled electrodes from rat lumbar spinal cord slices. In 19 of 63 neurones, Hcrt-2 (30 nM to 1 microM) evoked an inward (excitatory) current accompanied by an increase in baseline noise. The inward current and noise were unaffected by TTX but were blocked by the P(2X) purinergic receptor antagonist suramin (300-500 microM). Hcrt-2 (30 nM to 1 microM) increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in the majority of neurones. The sIPSC increase was blocked by strychnine (1 microM) and by TTX (1 microM), suggesting that the increased sIPSC frequency was glycine and action potential dependent. Hcrt-2 increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in a few neurones but had no effect on dorsal root-evoked EPSCs in these or in other neurones. Neurones located in outer lamina II, particularly radial and vertical cells, were most likely to respond to Hcrt-2. We conclude that Hcrt-2 has excitatory effects on certain SDH neurones, some of which exert inhibitory influences on other cells of the region, consistent with the perspective that hypocretin has a role in orchestrating reactions related to arousal, including nociception, pain and temperature sense.
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PMID:Hypocretin-2 (orexin-B) modulation of superficial dorsal horn activity in rat. 1179 Aug 16

1. Orexin-A and orexin-B (also known as hypocretin-1 and hypocretin-2) are hypothalamic peptides and regulate feeding behaviour, energy metabolism and the sleep-wake cycle. Orexin-A binds equally to both orexin-1 and orexin-2 receptors, while orexin-B has a preferential affinity for orexin-2 receptors. 2. Orexins are also known to be concentrated in superficial laminae of the spinal dorsal horn, and orexin-A and orexin-1 receptors are found in the dorsal root ganglion cells. 3. In the present study, the authors examined the effect of intrathecal injection of either orexin-A or orexin-B in the rat formalin test (a model of inflammatory pain) and in the rat hot plate test. The paw formalin injection induces biphasic flinching (phase 1: 0-6 min; phase 2: 10-60 min) of the injected paw. 4. Intrathecal injection of orexin-A, but not orexin-B, decreased the sum of flinches in phases 1 and 2 in the formalin test and increased the hot plate latency. These effects of orexin-A were completely antagonized by pre-treatment with SB-334867, a selective orexin-1 receptor antagonist. Intrathecal injection of SB-334867 alone had no effect in the formalin test or in the hot plate test. 5. Intrathecal injection of orexin-A suppressed the expression of Fos-like immunoreactivity (Fos-LI), induced by paw formalin injection, in laminae I-II of L4-5 of the spinal cord. 6. These data suggest that the spinal orexin-1 receptor is involved in the nociceptive transmission and that the activation of the spinal orexin-1 receptor produces analgesic effects in the rat formalin test and in the rat hot plate test.
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PMID:Analgesic effect of intrathecally administered orexin-A in the rat formalin test and in the rat hot plate test. 1220 73

Recently, an orphan G protein coupled receptor (GPCR) termed NPGPR was described. A shorter variant of this receptor lacking exon 1 was shown to have subnanomolar affinity for neuropeptide FF (NPFF), a pain modulatory peptide, and therefore was named NPFF(2) receptor. Here, we characterize the full-length cloned NPGPR and identify a novel short form lacking exon 2 with a differential pattern of mRNA abundance in several tissues and organs. The NPGPR is most similar to the recently cloned neuropeptide FF (NPFF) receptor which lacks exon 1, but also shows high homology to the orexin and neuropeptide Y (NPY) receptor families, two neuropeptides involved in food intake regulation. Therefore, we used binding studies to examine the interaction of NPFF, orexin and NPY with the NPGPR. [125I] NPFF was displaced by NPFF with an IC(50) of 14.7 +/- 8.8 nM, whereas [125I] Orexin B was displaced by Orexin B with an IC(50) of 415 +/- 195 nM. We conclude that orexins interact with the NPGPR and that the affinity of NPFF for NPGPR is approximately 100-fold lower than for the NPFF2 receptor. We postulate that NPGPR is a splice variant of the family of NPFF receptors and displays a binding profile different from the other members of the NPFF receptor family due to the presence of exon 1. In order to evaluate whether NPGPR levels are affected by the feeding status, we examined the mRNA level using real-time PCR in two feeding models, i.e. before and after diet-induced body weight increase as well as after chronic food restriction in rats. However, hypothalamic NPGPR mRNA was unchanged in both models. Therefore, our evidence does not support the hypothesis that NPGPR is involved in feeding regulation.
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PMID:Characterization of the NPGP receptor and identification of a novel short mRNA isoform in human hypothalamus. 1260 45

Orexin-A has been reported to produce an analgesic effect in the hot plate test and in the inflammatory pain models. In the present study, the authors examined the effect of orexin-A on the mechanical allodynia induced by partial sciatic nerve ligation (a model of neuropathic pain) in the rat. Partial sciatic nerve ligation is created by tight ligation of one-third or one-half of the right sciatic nerve. Orexin-A was administered intrathecally or intracerebroventricularly 7 days after a partial sciatic nerve injury. Either intrathecal or intracerebroventricular injection of orexin-A attenuated the level of mechanical allodynia induced by partial sciatic nerve ligation. These data suggest that either intrathecal or intracerebroventricular injection of orexin-A is a new therapeutic approach to treating mechanical allodynia caused by nerve injury.
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PMID:Anti-mechanical allodynic effect of intrathecal and intracerebroventricular injection of orexin-A in the rat neuropathic pain model. 1287 16

The ultrastructure and synaptic relationships of orexin A-like immunoreactive neuronal fibers in the dorsal horn of the rat cervical spinal cord were examined at both the light and electron microscopic levels. At the light microscopic level, many intensely immunostained orexin A-like fibers were found, while at the electron microscopic level, immunoreactivity in these fibers was mostly confined to axon terminals. Most of the axon terminals contained dense-cored vesicles. Immunoreactive and immunonegative dense-cored vesicles were occasionally found within the same orexin A-like immunoreactive axon terminals, which were often found making synapses with immunonegative dendrites. These synapses were both asymmetric and symmetric, with the asymmetric ones predominant. Orexin A-like immunoreactive processes that contained no synaptic vesicles were also found with less frequency. These processes were also observed receiving synaptic inputs from immunonegative axon terminals, but the synapses were mostly asymmetric. Sometimes, such processes were found to receive multiple synaptic inputs for which the presynaptic immunonegative axon terminals could make synapses on other immunonegative dendrites simultaneously. Occasionally, synapses between the orexin A-like immunoreactive axon terminals and orexin A-like immunoreactive processes containing no synaptic vesicles were also found. The present results provide solid morphological evidence that orexin A may be involved in pain-inhibition mechanisms in the spinal cord and suggest that this function may be complex and occur in conjunction with the regulatory effects of other neurotransmitters.
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PMID:Immunoelectron microscopic examination of orexin-like immunoreactive fibers in the dorsal horn of the rat spinal cord. 1449 49

Orexin A and B (hypocretin 1 and 2) are the endogenous ligands of orexin receptors, a G-protein-coupled orphan receptor family containing orexin 1 (OX1) and orexin 2 (OX2) types. Orexin A induces analgesia in acute and inflammatory pain models. We further elucidated the possible antiallodynic effect of intrathecal orexins in a rat model of postoperative pain. Mechanical allodynia was induced by incising the rat hind paw and evaluated with the withdrawal threshold to von Frey filament stimulation. Intrathecal orexin A (0.03-1 nmol) and orexin B (0.1-3 nmol) dose dependently attenuated the incision-induced allodynia. Orexin A (ED50 = 0.06 nmol) is more potent than orexin B. The effects of orexin A and B were abolished by their respective antibodies, but not by naloxone, and were attenuated by suramin and strychnine, the P2X purinergic and glycine receptor antagonists, respectively. SB-334867, an OX1 receptor antagonist, at 30 nmol completely blocked the effect of orexin A but, even at 100 nmol, only partially antagonized the effect of orexin B. Orexin A antibody, SB-334867, suramin, strychnine, or naloxone enhanced the incision-induced allodynic response. It is concluded that intrathecal orexins reduce incision-induced allodynia through OX1 receptors. Glycine and P2X purinergic receptors, but not opioid receptors, might be involved in the antiallodynic effects of orexins. Endogenous orexin might be released after incision injury to activate the spinal OX1 receptors as an endogenous analgesic protector.
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PMID:Antiallodynic effects of intrathecal orexins in a rat model of postoperative pain. 1455 Dec 90

Orexin-A, a hypothalamic peptide found in the neurons of the lateral hypothalamus, has been shown to modulate pain. We examined whether orexin could alleviate heat-evoked hyperalgesia in rats caused by chronic constriction injury (CCI) of the sciatic nerve. Orexin-A, orexin-B, the vehicle, or orexin-A-antiserum was intrathecally administered to CCI rats. Paw withdrawal latency (PWL) was measured from 30 to 300 minutes after injection, which was repeated for 2 days. Orexin-A administration normalized deltaPWL (PWL in the CCI side minus PWL in the control side) and inhibited heat-evoked hyperalgesia in CCI rats, while orexin-A antiserum inhibited the normalization of heat-evoked hyperalgesia caused by orexin-A two-fold. In contrast, orexin-B had no significant effect. These results suggest that orexin-A may be applicable for treatment of neuropathic pain.
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PMID:Analgesic effect of intrathecal administration of orexin on neuropathic pain in rats. 1511 38

The novel neuropeptides orexin A and B are selectively synthesised in the lateral and posterior hypothalamus and are involved in hypothalamic regulation of autonomic and neuroendocrine functions. Recent findings point also to a role in nociception. As the posterior hypothalamus is involved in the central modulation of nociception we studied the effects of hypocretin/orexin receptor activation in the posterior hypothalamic area (PH) of the rat on dural nociceptive input. Orexins were microinjected into the PH and the effects on responses of neurones in the caudal trigeminal nucleus studied. Injection of orexin A decreased the A- and C-fibre responses to dural electrical stimulation as well as spontaneous activity. Responses to noxious thermal stimulation of the facial skin were also decreased by orexin A. Injection of orexin B into the PH, however, elicited increased responses to dural stimulation in A- and C-fibre responses and resulted in increased spontaneous activity. Responses to facial thermal stimulation were also increased by orexin B. Control injection of saline into the PH had no significant effect. The results show a differential modulation of dural nociceptive input by orexin A and B receptor activation in the PH. The results support the role of the PH in the nociceptive processing of meningeal input. As both peptides are also involved in hypothalamic regulation of neuroendocrine and autonomic functions, orexinergic mechanisms in the PH may provide a link for endocrine and autonomic changes as well as nociceptive phenomena seen in primary headache disorders.
Pain 2004 Jun
PMID:Differential modulation of nociceptive dural input to [hypocretin] orexin A and B receptor activation in the posterior hypothalamic area. 1515 98


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