Sexually dimorphic nociception and opioid antinociception is very pervasive but poorly understood. We had demonstrated that spinal morphine in females, not males, requires the concomitant activation of μ- κ-opioid receptors (MOR KOR, respectively). This finding suggests an interrelationship between MOR KOR females manifest males. Here, we show expression a MOR/KOR heterodimer vastly more prevalent cord proestrous vs. diestrous Cross-linking experiments combination with vivo pharmacological...

We previously demonstrated that the spinal cord κ-opioid receptor (KOR) and μ-opioid (MOR) form heterodimers (KOR/MOR). KOR/MOR formation associated KOR dependency of morphine antinociception are most robust during proestrus. Using Sprague Dawley rats, we now demonstrate (1) synthesis estrogen is critical to these processes, (2) blockade either (ER) α-, β-, or G-protein-coupled ER1 progesterone (PR) substantially reduces eliminates mediation by antinociception. Effects blocking ERs were...

Simulation of the pregnancy blood concentration profile 17beta-estradiol (E(2)) and progesterone (P) in nonpregnant ovariectomized rats has been shown to result a significant elevation nociceptive response thresholds. The present report demonstrates that spinal opioid antinociceptive responsiveness these ovarian steroids is not sex-specific. Treatment orchidectomized sexually mature males with an analogous regimen E(2) P also elicits antinociception, robustness temporal which comparable...

Current evidence for sex-based nociception and antinociception, largely confined to behavioral measures of pain sensitivity, chronic syndromes, analgesic efficacy, provides little mechanistic insights into biological substrates causally associated with sexual dimorphic experience. Spinal cord has been shown be a central nervous system region in which regulation opioid antinociceptive manifest dimorphism. This site was therefore chosen explore whether or not differential mechanisms underlie...

Abstract The gene encoding the mu‐opioid receptor (MOR) generates a remarkable diversity of subtypes, functional significance which remains largely unknown. structure MOR could be critical determinant functionality and its adaptations to chronic morphine exposure. As antinociception has sexually dimorphic dimensions, we determined influence sex, stage estrus cycle, systemic on levels splice variant mRNA in rat spinal cord. Chronic influenced expression rMOR ‐1B2 ‐1C1 profoundly sex‐dependent...

Cholecystokinin octapeptide (CCK-8) is reported to antagonize the analgesic effect produced by mu- and kappa- but not delta-opioid agonist in spinal cord. However, mechanisms of interaction remain obscure. In present study, whole-cell patch-clamp recording was performed on acutely isolated rat dorsal root ganglion (DRG) neurons evaluate effects highly specific mu-opioid ohmefentanyl DPDPE voltage-gated calcium channels possible between CCK-8 receptor or receptor. The results indicated that...

The role of dynorphin A (1-17; Dyn) and its associated kappa opioid receptor (KOR) in nociception represents a longstanding scientific conundrum: Dyn KOR (Dyn/KOR) have variously been reported to inhibit, facilitate, or no effect on pain. We investigated whether interactions between sex pain type (which are usually ignored) influenced Dyn/KOR-mediated antinociception. Blockade the spinal <i>α</i>₂-noradrenergic (<i>α</i>₂-NAR) using yohimbine elicited comparable release...

Caveolin-1 is the predominant structural protein of caveolae, a subset (lipid) membrane rafts that compartmentalize cell signaling. binds most to G protein-coupled receptors and their signaling partners, thereby enhancing interactions among cascade components relative activation specific pathways. This study reveals chronic opioid exposure μ-opioid receptor (MOR) expressing Chinese hamster ovary cells (MOR-CHO) in vivo morphine rat spinal cord augmented recruitment multiple MOR-adenylyl...

Pharmacological and behavioral studies suggest that spinal δ- κ-opioid antinociceptive systems are functionally associated with ovarian sex steroids. These interactions can be demonstrated specifically during pregnancy or hormone-simulated (HSP). The analgesia both conditions abolished by blockade of either receptors δ-opioid (DOR). Furthermore, dynorphin (DYN) release (<i>J Pharmacol Exp Ther</i> 298:1213–1220, 2001) the processing DYN precursor Neurochem</i> 65:1374–1380, 1995)...

Opioids inhibit release of primary afferent transmitters but it is unclear whether the converse occurs. To test hypothesis that influence opioid-ergic tone, we studied functional and anatomical relationships between pituitary adenylyl cyclase-activating polypeptide (PACAP) dynorphin 1-17 (Dyn) in spinal cord. We found activation PACAP-specific receptor PAC₁ (PAC₁R) inhibited, whereas PAC₁R blockade augmented, Dyn. It noteworthy formalin-induced pain model...

Pregnancy is associated with an antinociception that multifactorial and results from spinal (kappa/delta) opioid antinociceptive pathways as well peripheral processes (ovarian sex steroids, uterine afferent neurotransmission). The present provide the first indication full manifestation of pregnancy-induced analgesia also requires a supraspinal component. gestation or its hormonal simulation (via estrogen progesterone administration; HSP) substantially attenuated (>/=60%) following blockade...

We studied adaptations to acute precipitated opioid withdrawal of spinal μ-opioid receptor (MOR)-coupled regulation the release endomorphin 2 (EM2). The this highly MOR-selective endogenous from opioid-naive tissue male rats is subjected MOR-coupled positive as well negative modulation via cholera toxin-sensitive G_s and pertussis G_i/G_o, respectively. net effect concomitant bidirectional inhibitory. pleiotropic EM2 retained in opioid-withdrawn rats, but...

The magnitude of antinociception elicited by intrathecal endomorphin 2 (EM2), an endogenous mu-opioid receptor (MOR) ligand, varies across the rat estrous cycle. We now report that phasic changes in analgesic responsiveness to spinal EM2 result from plastic interactions within a novel membrane-bound oligomer containing estrogen receptors (mERs), aromatase (aka synthase), metabotropic glutamate 1 (mGluR1), and MOR. During diestrus, mERs, activated locally synthesized estrogens, act with...

We previously showed that intrathecal application of endomorphin 2 [EM2; the highly specific endogenous μ-opioid receptor (MOR) ligand] induces antinociception varies with stage rat estrous cycle: minimal during diestrus and prominent proestrus. Earlier studies, however, did not identify proestrus-activated signaling strategies enable spinal EM2 antinociception. now report in female rats, increased dynorphin release κ-opioid (KOR) signaling, as well emergence glutamate-activated metabotropic...

Abstract Rapid-signaling membrane estrogen receptors (mERs) and aromatase (Aro) are present throughout the central nervous system (CNS), enabling acute regulation of CNS estrogenic signaling. We previously reported that spinal Aro (mAro) mERα oligomerize (1). As their organizational relationship would likely influence functions locally produced estrogens, we quantified mAro physically associated nonassociated in two functionally different regions rat CNS: cord, which has predominantly neural...

&lt;b&gt;&lt;i&gt;Background/Aims:&lt;/i&gt;&lt;/b&gt; Male and female rats differ in their ability to utilize spinal endomorphin 2 (EM2; the predominant mu-opioid receptor ligand cord) mechanisms that underlie EM2 analgesic responsiveness. We investigated relevance of estrogen receptors (ERs) vivo regulation release. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; ER antagonists were administered directly lumbosacral cord male rats, intrathecal perfusate was collected, resulting changes...

Phosphoinositide turnover and calcium mobilization are fundamental determinants of acute chronic opioid effects. Phosphoinositide-specific phospholipase C (PLC) key signaling enzymes that play a pivotal role in mediating modulation inositol trisphosphate production cytosolic distribution, substrates for many Notably, phosphorylation the β isoforms PLC, by kinases up-regulated after morphine, is potent modality their regulation. Direct assessment PLCβ1 PLCβ3 guinea pig longitudinal muscle...

Abstract We recently demonstrated in rat spinal cord that a regimen of escalating doses systemic morphine, analogous to regimens used clinically for chronic pain management, selectively up‐regulates the mu‐opioid receptor (MOR) splice variants MOR‐1B2 and MOR‐1C1 mRNA functional protein. This study investigated potential relevance up‐regulating ability morphine shift MOR signaling from predominantly G i /G o inhibitory s stimulatory. Specifically, we tested hypotheses induces phosphorylation...