Dynorphin
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Dynorphins (Dyn) are a class of
opioid peptides Opioid peptides are peptides that bind to opioid receptors in the brain; opiates and opioids mimic the effect of these peptides. Such peptides may be produced by the body itself, for example endorphins. The effects of these peptides vary, but th ...
that arise from the precursor
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
prodynorphin Prodynorphin, also known as proenkephalin B, is an opioid polypeptide hormone involved with chemical signal transduction and cell communication. The gene for prodynorphin is expressed in the endometrium and the striatum, and its gene map locus is 20 ...
. When prodynorphin is cleaved during processing by
proprotein convertase 2 Proprotein convertase 2 (PC2) also known as prohormone convertase 2 or neuroendocrine convertase 2 (NEC2) is a serine protease and proprotein convertase PC2, like proprotein convertase 1 (PC1), is an enzyme responsible for the first step in the m ...
(PC2), multiple active peptides are released:
dynorphin A Dynorphin A is a dynorphin, an endogenous opioid peptide with the amino acid sequence: Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys. Dynorphin A1–8 is a truncated form of dynorphin A with the amino acid sequence: Tyr-Gly-Gly-Phe-Leu-Ar ...
,
dynorphin B Dynorphin B, also known as rimorphin, is a form of dynorphin and an endogenous opioid peptide with the amino acid sequence Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr. Dynorphin B is generated as a proteolytic cleavage product of leumorph ...
, and α/ β-neo-endorphin. Depolarization of a
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
containing prodynorphin stimulates PC2 processing, which occurs within synaptic
vesicles Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle ; In human embryology * Vesicle (embryology), bulge-like features o ...
in the
presynaptic terminal Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...
. Occasionally, prodynorphin is not fully processed, leading to the release of “big dynorphin.” “Big Dynorphin” is a 32-amino acid molecule consisting of both dynorphin A and dynorphin B. Dynorphin A, dynorphin B, and
big dynorphin Big dynorphin is an endogenous opioid peptide of the dynorphin family that is composed of both dynorphin A and dynorphin B. Big dynorphin has the amino acid sequence Protein primary structure is the linear sequence of amino acids in a peptide or ...
all contain a high proportion of basic amino acid residues, in particular lysine and arginine (29.4%, 23.1%, and 31.2% basic residues, respectively), as well as many hydrophobic residues (41.2%, 30.8%, and 34.4% hydrophobic residues, respectively). Although dynorphins are found widely distributed in the CNS, they have the highest concentrations in the
hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
,
medulla Medulla or Medullary may refer to: Science * Medulla oblongata, a part of the brain stem * Renal medulla, a part of the kidney * Adrenal medulla, a part of the adrenal gland * Medulla of ovary, a stroma in the center of the ovary * Medulla of t ...
,
pons The pons (from Latin , "bridge") is part of the brainstem that in humans and other bipeds lies inferior to the midbrain, superior to the medulla oblongata and anterior to the cerebellum. The pons is also called the pons Varolii ("bridge of Va ...
,
midbrain The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal (alertness), and temperature regulation. The name comes from the Greek ''mesos'', " ...
, and
spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spi ...
. Dynorphins are stored in large (80-120 nm diameter) dense-core vesicles that are considerably larger than vesicles storing
neurotransmitters A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neur ...
. These large dense-core vesicles differ from small synaptic vesicles in that a more intense and prolonged stimulus is needed to cause the large vesicles to release their contents into the
synaptic cleft Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...
. Dense-core vesicle storage is characteristic of opioid peptides storage. The first clues to the functionality of dynorphins came from Goldstein et al. in their work with opioid peptides. The group discovered an endogenous opioid peptide in the porcine pituitary that proved difficult to isolate. By sequencing the first 13 amino acids of the peptide, they created a synthetic version of the peptide with a similar potency to the natural peptide. Goldstein et al. applied the synthetic peptide to the guinea ileum longitudinal muscle and found it to be an extraordinarily potent opioid peptide. The peptide was called dynorphin (from the Greek ''dynamis'', meaning power) to describe its potency. Dynorphins exert their effects primarily through the
κ-opioid receptor The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP, is a G protein-coupled receptor that in humans is encoded by the ''OPRK1'' gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind op ...
(KOR), a
G-protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
. Two subtypes of KORs have been identified: K1 and K2. Although KOR is the primary receptor for all dynorphins, the peptides do have some affinity for the
μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical ...
(MOR),
δ-opioid receptor The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi/G0 and has enkephalins as its endogenous lig ...
(DOR), and the N-methyl-D-aspartic acid (
NMDA ''N''-methyl--aspartic acid or ''N''-methyl--aspartate (NMDA) is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unlike ...
)-type glutamate receptor. Different dynorphins show different receptor selectivities and potencies at receptors. Big dynorphin and dynorphin A have the same selectivity for human KOR, but dynorphin A is more selective for KOR over MOR and DOR than is big dynorphin. Big dynorphin is more potent at KORs than is dynorphin A. Both big dynorphin and dynorphin A are more potent and more selective than dynorphin B.


Production

Dynorphin is produced in many different parts of the nervous system, including the
hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
, the
striatum The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamate ...
, the
hippocampus The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...
and the
spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spi ...
. Gene expression patterns from the
Allen Brain Atlas The Allen Mouse and Human Brain Atlases are projects within the Allen Institute for Brain Science which seek to combine genomics with neuroanatomy by creating gene expression maps for the mouse and human brain. They were initiated in September 2 ...
es in mouse, macaque and humans can be see
here
Dynorphin has many different physiological actions, depending upon its site of production. * For example, dynorphin that is made in magnocellular
vasopressin Human vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the AVP gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then travel ...
neurons of the
supraoptic nucleus The supraoptic nucleus (SON) is a nucleus of magnocellular neurosecretory cells in the hypothalamus of the mammalian brain. The nucleus is situated at the base of the brain, adjacent to the optic chiasm. In humans, the SON contains about 3,000 n ...
is important in the patterning of electrical activity. Dynorphin produced in magnocellular
oxytocin Oxytocin (Oxt or OT) is a peptide hormone and neuropeptide normally produced in the hypothalamus and released by the posterior pituitary. It plays a role in social bonding, reproduction, childbirth, and the period after childbirth. Oxytocin ...
neurons is a
negative feedback Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused by ...
inhibitor of
oxytocin Oxytocin (Oxt or OT) is a peptide hormone and neuropeptide normally produced in the hypothalamus and released by the posterior pituitary. It plays a role in social bonding, reproduction, childbirth, and the period after childbirth. Oxytocin ...
secretion. * Dynorphin produced in the
arcuate nucleus The arcuate nucleus of the hypothalamus (also known as ARH, ARC, or infundibular nucleus) is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several ...
and in
orexin Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone ("drop attacks" or cataplexy) ...
neurons of the
lateral hypothalamus The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA), contains the primary orexinergic nucleus within the hypothalamus that widely projects throughout the nervous system; this system of neurons mediates an array of cognit ...
affects the control of
appetite Appetite is the desire to eat food items, usually due to hunger. Appealing foods can stimulate appetite even when hunger is absent, although appetite can be greatly reduced by satiety. Appetite exists in all higher life-forms, and serves to regu ...
.


Analgesia

Dynorphin has been shown to be a modulator of pain response. Han and Xie found that injecting dynorphin into the subarachnoid space of the rat spinal cord produced dose-dependent analgesia that was measured by tail-flick latency. Analgesia was partially eliminated by opioid antagonist naloxone. Han and Xie found dynorphin to be 6-10 times more potent than
morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a analgesic, pain medication, and is also commonly used recreational drug, recreationally, or to make ...
on a per mole basis. In addition, morphine tolerance did not reduce dynorphin-induced analgesia. Ren et al. demonstrated some of the complexities related to dynorphin induced analgesia. The authors found that combining subanalgesic levels of morphine and dynorphin A1-13, a version of dynorphin A containing only the first 13 amino acids of the peptide, in the rat spinal cord had additive effects. However, when dynorphin A1-13 was injected into the intracerebroventricular (ICV) region of the brain, it had an antagonist effect on morphine-induced analgesia. A study by Lai et al. found that dynorphin might actually stimulate pain. The group found that it acts on the bradykinin receptor as well as KOR. The N-terminal tyrosine of dynorphin A is necessary to activate opioid receptors such as KOR, but is unnecessary in binding to bradykinin receptors. Lai et al. studied the effects of dynorphin A2-13 that did not contain the N-terminal tyrosine. Based on the results of dynorphin A2-13, the authors proposed a mechanism in which dynorphin A activates bradykinin receptors and thus stimulates pain response. According to this mechanism, dynorphin activates bradykinin receptors, which triggers the release of calcium ions into the cell through voltage-sensitive channels in the cell membrane. Blocking bradykinin receptors in the lumbar region of the spinal cord reversed persistent pain. A multiple pathway system might help explain the conflicting effects of dynorphin in the CNS. Svensson et al. provided another possible mechanism by which dynorphin might cause pain in the spinal cord. The authors found that administration of truncated dynorphin A2-17, which does not bind to opioid receptors, causes an increase in phosphorylated p38 mitogen-activated protein kinase (MAPK) in microglia in the dorsal horn of the spinal cord. Activated p38 has been previously linked to the NMDA-evoked
prostaglandin The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derive ...
release, which causes pain. Thus, dynorphin could also induce pain in the spinal cord through a non-opioid p38 pathway. Other studies have identified a role for dynorphin and kappa opioid receptor stimulation in neuropathic pain. This same group also showed that the dynorphin-KOR system mediates
astrocyte Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of e ...
proliferation through the activation of p38 MAPK that was required for the effects of neuropathic pain on analgesic responses. Taken together, these reports suggest that dynorphin can elicit multiple effects on both Kappa opioid, and non-opioid pathways to modulate analgesic responses.


Addiction

Cocaine addiction results from complex molecular changes in the brain following multiple exposures to cocaine. Dynorphins have been shown to be an important part of this process. Although a single exposure to cocaine does not affect brain dynorphin levels, repeated exposures to the drug increases dynorphin concentrations in the
striatum The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamate ...
and
substantia nigra The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts of the substantia nigra app ...
in rats. One proposed molecular mechanism for increased dynorphin levels involves transcriptional regulation by
CREB CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first des ...
(3’, 5’-monophosphate response element binding protein). According to the model proposed by Carlezon et al., use of cocaine increases the expression of
cAMP Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
and cAMP-dependent protein kinase ( PKA). PKA leads to the activation of CREB, which increases the expression of dynorphin in the nucleus accumbens and dorsal striatum, brain areas important in addiction. Dynorphin decreases
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
release by binding to KORs on dopamine nerve terminals.


Cocaine

Carlezon et al. performed several experiments to validate this model. They found that, when mice were injected with cocaine, they preferred to be in the place where they were injected (showed stronger place preference) significantly more than control mice (injected with saline) did. However, in mice overexpressing CREB under a constitutive promoter, place aversion was observed. This indicates that increasing CREB reverses the positive effects of cocaine.
Northern blot The northern blot, or RNA blot,Gilbert, S. F. (2000) Developmental Biology, 6th Ed. Sunderland MA, Sinauer Associates. is a technique used in molecular biology research to study gene expression by detection of RNA (or isolated mRNA) in a sample ...
analysis several days after CREB overexpression showed a marked increase in dynorphin mRNA in the nucleus accumbens. Blocking KORs with an antagonist (norBNI) blocked the aversive effects caused by CREB overexpression. Thus, cocaine use ultimately appears to lead to an increase in the transcription of prodynorphin mRNA. Dynorphin inhibits dopamine release, which could account the reinforcing properties of cocaine. There is also evidence suggesting that increased amounts of dynorphin can protect humans from cocaine addiction. According to research at Rockefeller University, the gene for dynorphin is present in two versions: a “high output” and a “low output” functional variation. The high output functional variation of the gene contains polymorphisms in the promoter regions that are speculated to cause it to produce more copies of dynorphin mRNA, which would give people carrying this variation a “built-in defense system” against drug addiction.


Stress and depression

Land et al. first described a mechanism of dysphoria in which
corticotropin-releasing factor Corticotropin-releasing factor family, CRF family is a family of related neuropeptides in vertebrates. This family includes corticotropin-releasing hormone (also known as CRF), urotensin-I, urocortin, and sauvagine. The family can be grouped int ...
(CRF) provokes dynorphin release. While control mice displayed aversive behaviors in response to forced swim tests and foot shocks, mice lacking dynorphin did not show any such signs of aversion. They noted that injecting CRF led to aversive behaviors in mice with functional genes for dynorphin even in the absence of stress, but not in those with dynorphin gene deletions. Place aversion was eliminated when the receptor CRF2 was blocked with an antagonist. Together these results led Land et al. to conclude that dysphoric elements of stress occur when CRF2 stimulates dynorphin release and activates KOR. The group further postulated that this pathway might be involved in drug seeking behavior. In support of this, it was shown previously that stress can reinstate cocaine-seeking behavior in mice through a CRF mechanism. Dynorphin has also been shown to influence drug seeking behavior and is required for stress-induced, but not prime-induced, reinstatement of cocaine seeking. A downstream element of this pathway was later identified by Bruchas et al. The authors found that KOR activates p38, a member of the mitogen-activated protein kinase (MAPK) family, through phosphorylation. Activation of p38 is necessary to produce KOR-dependent behaviors. Because of its role in mediating
dysphoria Dysphoria (; ) is a profound state of unease or dissatisfaction. It is the semantic opposite of euphoria. In a psychiatric context, dysphoria may accompany depression, anxiety, or agitation. In psychiatry Intense states of distress and unea ...
, dynorphin has also been investigated in relation to depression. Newton et al. studied the effects of CREB and dynorphin on
learned helplessness Learned helplessness is the behavior exhibited by a subject after enduring repeated aversive stimuli beyond their control. It was initially thought to be caused by the subject's acceptance of their powerlessness, by way of their discontinuing atte ...
(an animal model for depression) in mice. Overexpression of dominant negative CREB (mCREB) in transgenic mice had an antidepressant effect (in terms of behavior), whereas overexpressing wild-type CREB caused an increase in depression-like symptoms. As described previously, CREB increases transcription of prodynorphin, which gives rise to different dynorphin subtypes. Newton et al. supported this mechanism, as the mCREB was colocalized with decreased expression of prodynorphin. Also, direct antagonism of dynorphin caused antidepressant-like effects similar to those seen with mCREB expression. Thus, the CREB-dynorphin pathway regulates mood as well as cocaine rewards. Shirayama et al. used several animal depression models in rats to describe the effects of dynorphins A and B in depression. The authors found that learned helplessness increases the levels of dynorphins A and B in the hippocampus and nucleus accumbens and that injecting KOR antagonist norBNI induces recovery from learned helplessness. Immobilization stress causes increases in the levels of both dynorphins A and B in the hippocampus and nucleus accumbens. Forced swim stress increases the levels of dynorphin A in the hippocampus. Shirayama et al. concluded that both dynorphins A and B were important in stress response. The authors proposed several mechanisms to account for the effects of the KOR antagonist norBNI on learned helplessness. First, increased dynorphin levels block the release of
glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
, a neurotransmitter involved in plasticity in the hippocampus, which would inhibit new learning. Blocking dynorphin effects would allow glutamate to be released and restore functional plasticity in the hippocampus, reversing the phenomenon of learned helplessness. In addition, blocking dynorphin would enhance dopamine signaling and thus reduce depressive symptoms associated with stress. The authors suggest that KOR antagonists might have potential in treating depression in humans.


Appetite and circadian rhythms

Dynorphins are important in maintaining
homeostasis In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
through appetite control and
circadian rhythms A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous) and responds to ...
. Przewlocki et al. found that, during the day, dynorphins are naturally elevated in the neurointermediate lobe of the pituitary (NI pituitary) and depressed in the hypothalamus. This pattern is reversed at night. In addition, mice deprived of food and water, or of water alone, had increased levels of dynorphin in the hypothalamus during the day. Deprivation of water alone also decreased the dynorphin levels in the NI pituitary. These findings led Przewlocki et al. to conclude that dynorphins are essential in maintaining homeostasis. Dynorphin has been implicated as an appetite stimulant. A number of studies in rats have shown that increasing the dynorphin levels stimulates eating. Opioid antagonists, such as
naloxone Naloxone, sold under the brand names Narcan (4 mg) and Kloxxado (8 mg) among others, is a medication used to reverse or reduce the effects of opioids. It is commonly used to counter decreased breathing in opioid overdose. Effects begin withi ...
, can reverse the effects of elevated dynorphin. This inhibition is especially strong in obese animals or animals that have access to particularly appealing food. Inui et al. found that administering dynorphin to dogs increased both their food and water intake. Dynorphin plays a role in the eating behavior of hibernating animals. Nizeilski et al. examined dynorphin levels in the ground squirrel, which undergoes periods of excessive eating and periods of starvation before winter. They found that dynorphin levels increased during the starvation periods. Berman et al. studied the levels of dynorphin during periods of food restriction. The group found that while food did not alter the expression of dynorphin B, it increases dynorphin A levels in several rat brain regions (
hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
,
nucleus accumbens The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for " nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hypot ...
, and bed nucleus of the stria terminalis). Recent research on dynorphin knockout mice did not find differences between knockout and control animals in food intake, but found that fat storage was reduced in male knockout mice. Fatty acids were oxidized more quickly in knockout animals. Studies have also shown that ingesting a high-fat diet increases the gene expression of dynorphin in the hypothalamus. Thus, dynorphin may cause overeating when a high-fat diet is available. Morley & Levine were the first to describe the role of opioid peptides in stress-related eating. In their study, mice had their tails pinched (causes stress), which induced eating. Stress-related eating was reduced by injecting naloxone, an opioid peptide antagonist. Mandenoff et al. proposed that, although endogenous opioids are not necessary to maintain body weight and energy expenditure under predictable circumstances, they become activated under stressful conditions. They found that endogenous opioids, such as dynorphin, stimulate appetite and decrease energy expenditure. Taken together, the studies above suggest an important evolutionary mechanism in which more food is eaten, more nutrients are stored, and less energy is expended by an organism during times of stress.


Temperature regulation

In addition to their role in weight control, dynorphins have been found to regulate body temperature. Opioid peptides were first investigated in
hyperthermia Hyperthermia, also known simply as overheating, is a condition in which an individual's body temperature is elevated beyond normal due to failed thermoregulation. The person's body produces or absorbs more heat than it dissipates. When extreme ...
, where it was found that MOR agonists stimulate this response when injected into the periaqueductal gray (PAG) region of the brain. Xin et al. showed that delivery of dynorphin A1-17 (a KOR agonist) through
microdialysis Microdialysis is a minimally-invasive sampling technique that is used for continuous measurement of free, unbound analyte concentrations in the extracellular fluid of virtually any tissue. Analytes may include endogenous molecules (e.g. neurotra ...
into the PAG region induced hypothermia in rats. The authors found that the severity of
hypothermia Hypothermia is defined as a body core temperature below in humans. Symptoms depend on the temperature. In mild hypothermia, there is shivering and mental confusion. In moderate hypothermia, shivering stops and confusion increases. In severe h ...
was proportional to the dose of dynorphin A1-17 administered. Hypothermia could be prevented by administering KOR antagonist norBNI to the rat. Xin et al. hypothesized that while MOR agonists mediate hyperthermia, KOR agonists, such as dynorphin, mediate hypothermia. Sharma and Alm found that subjecting rats to heat (38˚C) caused dynorphins to be upregulated in the cerebral cortex, hippocampus, cerebellum, and the brain stem. Further, authors found that administration of nitric oxide synthase (NOS) inhibitors reduced dynorphin A1-17 levels in the brain and attenuated symptoms related to heat stress. Sharma and Alm concluded that hyperthermia increases dynorphin levels, which may cause damage and promote heat stress reaction. They further hypothesized that
nitric oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...
was part of this mechanism. Ansonoff et al. found that hypothermic effects are mediated through K1 (κ-opioid receptor 1), but not K2. The authors applied a KOR agonist to K1 knockout mice, which eliminated hypothermic response. Thus, K2 does not appear to have a role in the hypothermic mechanism.


Clinical significance

Dynorphin derivatives are generally considered to be of little clinical use because of their very short duration of action.


References


External links

* {{Opioid receptor modulators Neurotransmitters Kappa-opioid receptor agonists Opioid peptides