Pramipexole decreases allodynia and hyperalgesia via NF-κB in astrocytes in rats with Parkinson's disease.

Pain is one of the principal non-motor symptoms of Parkinson's disease (PD), negatively impacting the patient's quality of life. This study aimed to demonstrate whether an effective dose of pramipexole (PPX) can modulate the NF-κB/p-p65 activation in glial cells (astrocytes and microglia) and diminish the hypersensitivity (allodynia and hyperalgesia) in male Wistar rats with PD. For this, 2 μl of 6-hydroxydopamine (6-OHDA, 8 μg/μL/0.

Hypothalamic cerebrospinal fluid-contacting neurons project to the rostral agranular insular cortex: An immunofluorescence and ultrastructural analysis in the rat.

Cerebrospinal fluid-contacting neurons (CSF-cNS) are considered mechanoreceptors and chemoreceptors involved in detecting changes in CSF circulation. However, considering that recent data suggest that this type of cell could exert an active response when an external stimulus is sensed, identification of CSF-cNS may be relevant. In this regard, some data suggest that a neuronal connection exists between the ventral region of the hypothalamic paraventricular nucleus (PVN) and rostral agranular insular cortex (RAIC); indeed, a potential CSF-cNS is hypothesized.

Hypothalamic Paraventricular Stimulation Inhibits Nociceptive Wide Dynamic Range Trigeminocervical Complex Cells via Oxytocinergic Transmission.

Oxytocinergic transmission blocks nociception at the peripheral, spinal, and supraspinal levels through the oxytocin receptor (OTR). Indeed, a neuronal pathway from the hypothalamic paraventricular nucleus (PVN) to the spinal cord and trigeminal nucleus caudalis (Sp5c) has been described. Hence, although the trigeminocervical complex (TCC), an anatomical area spanning the Sp5c, C1, and C2 regions, plays a role in some pain disorders associated with craniofacial structures (e.

The role of the endocannabinoid 2-arachidonoylglycerol in the in vivo spinal oxytocin-induced antinociception in male rats.

Oxytocin receptor (OTR) activation at the spinal level produces antinociception. Some data suggest that central OTR activation enhances social interaction via an increase of endocannabinoids (eCB), but we do not know if this could occur at the spinal level, modulating pain transmission. Considering that oxytocin via OTR stimulates diacylglycerol formation, a key intermediate in synthesizing 2-arachidonylglycerol (2-AG), an eCB molecule, we sought to test the role of the eCB system on the spinal oxytocin-induced antinociception.

The differential contribution of spinal α- and α-adrenoceptors in tonic and acute evoked nociception in the rat.

Spinal α-adrenoceptor induces analgesia by neuronal inhibition of primary afferent fibers. This family receptor coupled to G proteins can be subdivided into three functional subtypes: α, α and α-adrenoceptors, and current evidence on spinal analgesia supports the relevance of α and seems to exclude the role of α, but the functional contribution of α-adrenoceptors remains elusive. The present study was designed to pharmacologically dissect the contribution of spinal α-adrenoceptor subtypes modulating tonic or acute peripheral nociception.

The glial cell's role in antinociceptive differential effects of oxytocin upon female and male rats.

Background: Sex plays a crucial role in pain processing and response to analgesic drugs. Indeed, spinal glia seems to be significant in the sexual dimorphism observed in the above effects. Recently, studies have associated oxytocin with antinociceptive effects, but these have been mainly performed in male animals; consequently, the influence of sex has been poorly explored.

Ultrastructural Evidence for Oxytocin and Oxytocin Receptor at the Spinal Dorsal Horn: Mechanism of Nociception Modulation.

Oxytocin is a hypothalamic neuropeptide involved in the inhibition of nociception transmission at spinal dorsal horn (SDH) level (the first station where the incoming peripheral signals is modulated). Electrophysiological, behavioral, and pharmacological data strongly support the role of this neuropeptide and its receptor (the oxytocin receptor, OTR) as a key endogenous molecule with analgesic properties. Briefly, current data showed that oxytocin release from the hypothalamus induces OTR activation at the SDH, inducing selective inhibition of the nociceptive Aδ- and C-fibers (probably peptidergic) activity, but not the activity of proprioceptive fibers (i.

Dissection of Two Intracellular Pathways Involved in the Spinal Oxytocin-Induced Antinociception in the Rat.

Behavioral and electrophysiological data show that at the spinal level, oxytocin inhibits pain transmission by activation of oxytocin receptors (OTRs). Canonically, OTRs are coupled to G proteins, which induce a rise of intracellular Ca by activating the phospholipase C (PLC). However, data showed that OTRs cause a plethora of intracellular events, some related to the activation of G proteins.

An outlook on the trigeminovascular mechanisms of action and side effects concerns of some potential neuropeptidergic antimigraine therapies.

: In addition to serotonin (5-hydroxytryptamine; 5-HT) and other (neuro)mediators, the role of neuropeptides in migraine pathophysiology is relevant. Indeed, while some molecules interfering with calcitonin gene-related peptide (CGRP) transmission have recently been approved for clinical antimigraine use, other neuropeptides with translational use are in the pipeline. Among others, hypothalamic neuropeptides such as pituitary adenylate cyclase-activating peptide (PACAP), oxytocin (OT), and orexins stand out as potential novel targets to treat this neurovascular disorder.

Cortical Modulation of Nociception.

Nociception is the neuronal process of encoding noxious stimuli and could be modulated at peripheral, spinal, brainstem, and cortical levels. At cortical levels, several areas including the anterior cingulate cortex (ACC), prefrontal cortex (PFC), ventrolateral orbital cortex (VLO), insular cortex (IC), motor cortex (MC), and somatosensory cortices are involved in nociception modulation through two main mechanisms: (i) a descending modulatory effect at spinal level by direct corticospinal projections or mostly by activation of brainstem structures (i.e.

Intrathecal Oxytocin Improves Spontaneous Behavior and Reduces Mechanical Hypersensitivity in a Rat Model of Postoperative Pain.

The first few days post-surgery, patients experience intense pain, hypersensitivity and consequently tend to have minor locomotor activity to avoid pain. Certainly, injury to peripheral tissues produces pain and increases sensitivity to painful (hyperalgesia) and non-painful (allodynia) stimuli. In this regard, preemptive pharmacological treatments to avoid or diminish pain after surgery are relevant.

Oxytocin prevents neuronal network pain-related changes on spinal cord dorsal horn in vitro.

Recently, oxytocin (OT) has been studied as a potential modulator of endogenous analgesia by acting upon pain circuits at the spinal cord and supraspinal levels. Yet the detailed action mechanisms of OT are still undetermined. The present study aimed to evaluate the action of OT in the spinal cord dorsal horn network under nociceptive-like conditions induced by the activation of the N-methyl-d-aspartate (NMDA) receptor and formalin injection, using calcium imaging techniques.

The Rostral Agranular Insular Cortex, a New Site of Oxytocin to Induce Antinociception.

The rostral agranular insular cortex (RAIC) is a relevant structure in nociception. Indeed, recruitment of GABAergic activity in RAIC promotes the disinhibition of the locus ceruleus, which in turn inhibits (by noradrenergic action) the peripheral nociceptive input at the spinal cord level. In this regard, at the cortical level, oxytocin can modulate the GABAergic transmission; consequently, an interaction modulating nociception could exist between oxytocin and GABA at RAIC.

Inhibition of nociceptive dural input to the trigeminocervical complex through oxytocinergic transmission.

Migraine is a complex brain disorder that involves abnormal activation of the trigeminocervical complex (TCC). Since an increase of oxytocin concentration has been found in cerebrospinal fluid in migrainous patients and intranasal oxytocin seems to relieve migrainous pain, some studies suggest that the hypothalamic neuropeptide oxytocin may play a role in migraine pathophysiology. However, it remains unknown whether oxytocin can interact with the trigeminovascular system at TCC level.

Recurrent antinociception induced by intrathecal or peripheral oxytocin in a neuropathic pain rat model.

The search for new ligands to treat neuropathic pain remains a challenge. Recently, oxytocin has emerged as an interesting molecule modulating nociception at central and peripheral levels, but no attempt has been made to evaluate the effect of recurrent oxytocin administration in neuropathic pain. Using male Wistar rats with spinal nerve ligation, we evaluated the effects of recurrent spinal (1 nmol; given by lumbar puncture) or peripheral (31 nmol; given by intraplantar injection in the ipsilateral paw to spinal nerve ligation) oxytocin administration on pain-like behavior in several nociceptive tests (tactile allodynia and thermal and mechanical hyperalgesia) on different days.

Effect of local infiltration with oxytocin on hemodynamic response to surgical incision and postoperative pain in patients having open laparoscopic surgery under general anesthesia.

Background: Preemptive analgesia encompasses different perioperative interventions that have the final aim of decreasing postoperative pain and improving recovery. Recently, peripheral analgesic effects of oxytocinergic modulation have been suggested. In this regard, we tested the potential analgesic effects of subcutaneous oxytocin (OT) infiltration in patients submitted to laparoscopic cholecystectomy.

Some Prospective Alternatives for Treating Pain: The Endocannabinoid System and Its Putative Receptors GPR18 and GPR55.

Marijuana extracts (cannabinoids) have been used for several millennia for pain treatment. Regarding the site of action, cannabinoids are highly promiscuous molecules, but only two cannabinoid receptors (CB and CB) have been deeply studied and classified. Thus, therapeutic actions, side effects and pharmacological targets for cannabinoids have been explained based on the pharmacology of cannabinoid CB/CB receptors.

Recurrent inhibition in the cerebral cortex.

Neuronal activity can be modulated by endogenous control mechanisms that either facilitate or suppress it. With this idea in mind, we attempted to evaluate and correlate spinal neuronal activity with the amplitude of corticogram (ECoG) event related potentials (ERP) in the presence of nociceptive stimulation in rats. We evaluated the ERP in response to noxious stimuli, endogenous analgesic actions, different frequencies, and heterotopic nociceptive stimulation, as well as in conjunction with recordings from neurons in the spinal cord that are activated by noxious stimuli.

Peptidergic nature of nociception-related projections from the hypothalamic paraventricular nucleus to the dorsal horn of the spinal cord.

Hypothalamic paraventricular nucleus (PVN) projections to the spinal dorsal horn (SDH) are related to antinociception. Several neuropeptides from this nucleus could be released to the spinal cord after nociceptive stimuli. Indeed, it has been shown that enkephalins, oxytocin and vasopressin could be released at this level.

Oxytocin inhibits the rat medullary dorsal horn Sp5c/C1 nociceptive transmission through OT but not V receptors.

The medullary dorsal horn (MDH or Sp5c/C1 region) plays a key role modulating the nociceptive input arriving from craniofacial structures. Some reports suggest that oxytocin could play a role modulating the nociceptive input at the MDH level, but no study has properly tested this hypothesis. Using an electrophysiological and pharmacological approach, the present study aimed to determine the effect of oxytocin on the nociceptive signaling in the MDH and the receptor involved.

Peripheral oxytocin receptors inhibit the nociceptive input signal to spinal dorsal horn wide-dynamic-range neurons.

Oxytocin (OT) has emerged as a mediator of endogenous analgesia in behavioral and electrophysiological experiments. In fact, OT receptors (OTRs) in the spinal dorsal horn participate in a selective inhibition of the neuronal activity mediated by Aδ and C fibers but not Aβ fibers. This study shows that OTRs are expressed in the terminal nerve endings and are able to inhibit nociceptive neuronal firing.

The rat corticospinal system is functionally and anatomically segregated.

The descending corticospinal (CS) projection has been considered a key element for motor control, which results from direct and indirect modulation of spinal cord pre-motor interneurons in the intermediate gray matter of the spinal cord, which, in turn, influences motoneurons in the ventral horn. The CS tract (CST) is also involved in a selective and complex modulation of sensory information in the dorsal horn. However, little is known about the spinal network engaged by the CST and the organization of CS projections that may encode different cortical outputs to the spinal cord.