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We have evaluated the effects of antagonists to the mu, kappa and opiate receptors on 'opioid' and 'non-opioid mediated' analgesia. Our findings indicate that mu receptors might mediate 'opioid' and kappa receptors 'non-opioid' analgesia. It is suggested that endogenous opiates that act on mu or kappa receptors could be responsible for the different types of stress-induced analgesia.
The effects of U-50, 488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl ]-benzeneacetamide, methane sulfonate, hydrate), a purported selective kappa (non-mu) opioid agonist on spontaneous locomotor activity were investigated using a multi-dimensional behavioral analyzer (Animex II). U-50,488H (1 mg/kg) failed to affect behavior in mice, however, 3 mg/kg significantly reduced rearing and grooming. In addition, 10 mg/kg markedly reduced linear locomotion, rearing and grooming. The behavioral depression induced by U-50,488H (10 mg/kg) was reversible by the opioid antagonist Mr2266 (10 mg/kg). These results suggest that the selective activation of the kappa (non-mu) opioid receptor by U-50,488H decreases linear locomotion, rearing and grooming in mice.
While the distribution of opioid receptors can be differentiated in the rat central nervous system, their precise localization has remained controversial, due, in part, to the previous lack of selective ligands and insensitive assaying conditions. The present study analyzed this issue further by examining the receptor selectivity of [3H]DAGO (Tyr-D-Ala-Gly-MePhe-Gly-ol), [3H]DPDPE (2-D-penicillamine-5-D-penicillamine-enkephalin), [3H]DSLET (Tyr-D-Ser-Gly-Phe-Leu-Thr) and [3H](-)bremazocine, and their suitability in autoradiographically labelling selective subpopulations of opioid receptors in rat brain. The results from saturation, competition, and autoradiographic experiments indicated that the three opioid receptor subtypes can be differentiated in the rat brain and that [3H]DAGO and [3H]DPDPE selectively labelled mu and delta binding sites, respectively. In contrast, [3H]DSLET was found to be relatively non-selective, and labelled both mu and delta sites. [3H]Bremazocine was similarly non-selective in the absence of mu and delta ligands and labelled all three opioid receptor subtypes. However, in the presence of 100 nM DAGO and DPDPE, concentrations sufficient to saturate the mu and delta sites, [3H]bremazocine did label kappa sites selectively. The high affinity [3H]bremazocine binding sites showed a unique distribution with relatively dense kappa labelling in the hypothalamus and median eminence, areas with extremely low mu and delta binding. These results point to the selectivity, under appropriate conditions, of [3H]DAGO, [3H]DPDPE and [3H]bremazocine and provide evidence for the differential distribution of mu, delta, and kappa opioid receptors in rat brain.
The effects of ethylketocyclazocine (EKC), Mr 2266 and naltrexone on the stereotyped behaviors induced by an intraperitoneal injection of phencyclidine (PCP) were examined. PCP-induced turning, backpedalling, head weaving and sniffing were antagonized by pretreatment with EKC (0.25-4.0 mg/kg). While pretreatment with Mr 2266 (2.5 mg/kg), a kappa selective antagonist, and naltrexone (10 mg/kg), a mu selective antagonist, failed to affect the PCP-induced stereotypy, Mr 2266 antagonized the suppressing effect of EKC on PCP-induced stereotypy. Taken into consideration, this suggests that kappa opioid agonists such as EKC antagonize PCP-induced stereotyped behaviors through a kappa opioid mechanism, and that the mu opioid receptor may not play an important role in the PCP-induced stereotypy in rats.
Quantitative autoradiography was used to examine the effects of dehydration on kappa-opiate receptor binding in the neural lobe of the pituitary in rats. Dehydration was produced by 5 days of water deprivation or ingestion of 2% saline. Brattleboro rats homozygous for diabetes insipidus were used as a model of chronically disturbed water balance. Slide-mounted pituitary sections were incubated with [3H]bremazocine using kappa-receptor-selective assay conditions. Binding in the neural lobe was quantified by densitometry of film autoradiographs. Specific [3H]bremazocine binding in neural lobe sections of control rats was 45.4 fmol/mg wet weight. In contrast, binding in neural lobe sections of water-deprived, saline-treated, and water-sated homozygous Brattleboro rats was lower by 50%, 35% and 37%, respectively. We suggest that chronic dehydration elevates levels of endogenous neurohypophyseal dynorphin and produces a down-regulation of kappa-opiate receptors in the neurohypophysis, a change in affinity of the receptors for kappa-agonists, or both.
Opiate agonists as well as opiate antagonists release adrenocorticotropic hormone (ACTH) through unknown central mechanisms. We examined the role of corticotropin releasing factor (CRF) in opioid actions on ACTH release. Rats were pretreated with a specific antiserum to rat CRF (r-CRF) prior to injection of the opiate antagonist naloxone or the opiate agonists morphine (mu-receptor agonist) or MR 2034 (kappa-receptor agonist). This abolished the increase in ACTH caused by naloxone or by the kappa-agonist. The mu-agonist morphine, however, caused a significant increase in ACTH in control- or r-CRF antiserum treated rats. We conclude that (a) endogenous opioids tonically inhibit the release of CRF, (b) kappa-agonists stimulate the release of CRF, and (c) mu-agonists release ACTH by acting additionally through CRF-independent mechanisms.
Chronic subcutaneous infusion with a low dose (0.5 mg/kg/h) of naloxone via minipumps blocked the antinociceptive action of the mu-agonist, morphine, without affecting that of the kappa-agonist, U50488H. This dose resulted in a transient suppression in the rate of body weight gain and a sustained reduction in daily food intake (FI) and water intake (WI): this decrease was seen in both the light and dark phases. Naloxone also resulted in a reduction in resting core temperature (TC) in the light but not the dark phase. It did not affect the weight loss or hypothermia which accompanied 24 h food and water deprivation. Naloxone did, however, suppress FI and WI following deprivation and inhibited the recovery of body weight thereafter. The influence of naloxone upon FI, WI, TC and body weight was dose-dependent over 0.05-0.50 mg/kg/h. Increasing the dose to 3.0 mg/kg/h eliminated the antinociceptive action of U50,488H revealing a blockade of kappa- (in addition to mu-) receptors. This higher dose was not more effective in reducing FI, WI, body weight and TC than 0.5 mg/kg/h. Further, treatment with MR 2266, an antagonist (or weak partial agonist) with a higher activity at kappa-receptors than naloxone, was not more effective than naloxone in reducing FI, WI and body weight: further, it did not affect TC. Moreover, chronic infusion of bremazocine, (a kappa-agonist and mu-antagonist) reduced WI, FI, body weight and TC by a magnitude comparable to that of naloxone. Finally, chronic infusion of the mu-agonist, sufentanyl, led to a sustained rise in TC. It is concluded, that: (1) mu-opioid receptors may play a major role in the modulation of daily FI and WI and of body weight in freely behaving rats: this action is expressed in both the light and dark phases of the cycle and maintained following deprivation. The data provide no evidence for (but do not exclude) a particular role of kappa-receptors. (2) mu-Receptors play a physiological role in the modulation of TC in the light but not the dark phase of the daily cycle.
Quantitative autoradiography was used to examine the characteristics of kappa-opiate receptor binding in neural lobe sections from dehydrated rats and water-sated homozygous Brattleboro rats. The density of kappa-sites was decreased by 40% and 44%, respectively, after 5 days of water deprivation or hypertonic saline. Both the density and affinity of kappa-receptor sites were lower in homozygous Brattleboro rats. We suggest that kappa-receptor down-regulation occurs as a result of elevated release of opioid peptides induced by chronic osmotic stimulation.
The opioid mu-agonist morphine, the delta-agonist [D-Ala2,D-Leu5]enkephalin (DADL) and the kappa-agonist bremazocine locally applied to the surface of turtle visual cortex inhibited the orthodromic evoked potential (EP; fast negative component N1). After application of the sigma-agonist SKF 10.047 the inhibition was followed by facilitation of EP. The lack of cross-desensitization to the inhibitory action of opioids upon EP indicates that the drugs exert their effects via different opioid receptors. Bremazocine and morphine predominantly inhibited the left cortical EP, whereas DADL was a potent inhibitor of the right cortical EP. Thus, the opioid receptors which modulate evoked electrical activity of the left visual cortex (LVC) apparently belong mostly to the kappa- and mu-type, while delta-receptors were predominantly responsible for the modulation of electrical activity in the right visual cortex (RVC). Besides, we have studied in vivo binding of the kappa-agonist [3H]ethylketocyclazocine ([3H]EKC) and the delta-agonist [3H]DADL to LVC and RVC. The binding was specific and could be accounted for by the interaction with membrane opioid receptors and/or specific uptake of these drugs by cortex cells. [3H]EKC and [3H]DADL exhibited a more effective binding to LVC and RVC membranes, respectively. The results obtained in vitro apparently indicate that LVC and RVC differ in the number of kappa- and delta-binding sites. Thus, turtle brain may have a side-specific mechanism for selective neurochemical regulation of neuron activity in LVC and RVC realized predominantly via kappa- and delta-receptors, respectively.
The kappa-agonists bremazocine and dynorphin(1-13), the sigma-agonist SKF 10.047 as well as the delta-agonists [D-Ala2,D-Leu5]-enkephalin (DADL) and Met-enkephalin, but not the mu-agonist morphine, applied subarachnoidally to the caudal portion of the transected spinal cord (at the T3-T4 level) induced postural asymmetry of the hind limbs in rats. Asymmetry was registered visually. The leg was regarded as flexed if its projection on the longitudinal axis of the animal was smaller than that of its counterpart. The side of the flexed leg depended upon the type of drug: bremazocine, dynorphin(1-13) and Met-enkephalin predominantly induced flexion of the right leg, SKF 10.047 induced flexion of the left leg (at some doses there is no side preference), while in the case of DADL the side of the flexed leg depended upon the dose of the drug. Comparison of electromyographic activity of the symmetric biceps and quadriceps femoris revealed that bremazocine considerably facilitates the flexion reflex of the right hind limb without affecting the left limb reflex. As a rule, a flexed leg determined visually exhibited higher EMG activity of the biceps femoris as compared with a symmetric one. The opiate antagonist naloxone significantly reduced the percentage of animals with postural asymmetry. The magnitude of asymmetry and the side of flexion were not constant in some animals, but changed with time. However, the mean magnitude of asymmetry, the percentage of animals with asymmetry and the left/right flexion ratio in each group of animals remained constant. The side of flexion also depended upon the level of spinal cord transection: bremazocine and Met-enkephalin injected subarachnoidally following transection at the T1-T4 and T5-T6 levels predominantly induced flexion of the right and the left leg, respectively. Asymmetry did not develop in physiologically intact animals given bremazocine, even if the spinal cord was cut later, i.e. transection of the spinal cord was necessary for the development of asymmetry. These data indicate that the neurons which maintain muscular tone of the hind limbs and which are located symmetrically to the sagittal plane, have different sensitivities to kappa-, sigma-, and delta-agonists. In most animals, neurons with a higher specificity to some agonist are localized on one side of the sagittal plane.
Rats placed in a cold environment (4 degrees C) for 2 h had a sustained increase in tail flick latency (TFL) as well as an increase in tail pinch latency (TPch) that was often biphasic with an early peak response at 15 min and a later, often higher, peak at 2 h. Plasma beta-endorphin levels after a modest increase at 5 min (24%) declined throughout the remaining time in the cold. The long-acting opioid antagonist naltrexone had no effect on TFL increases but led to greater increases in TPch (P less than 0.04). In morphine-tolerant rats TFL response was the same as in controls but TPch increases were greater (P less than 0.04). Rats exposed to 2 h of cold for 17 or 18 consecutive days generally developed tolerance to the analgesia of cold, i.e. TFL and TPch increases were diminished; however, the response to morphine on day 18 was the same as in rats never exposed to cold. Adrenalectomy and hypophysectomy led to significantly smaller increases in TFL (P less than 0.02 and P less than 0.001, respectively). The TPch response in contrast, was greater in adrenalectomized (P less than 0.001) and the same in hypophysectomized rats compared to sham controls. An opioid kappa receptor antagonist (Mr 1452) given prior to cold reduced both TFL and TPch response during the first hour. Thus the analgesia induced by cold appeared to shift from an early possibly kappa opioid to a later non-opioid form. The TFL effects seemed to be under hormonal influence while the TPch were not.
The density and distribution of mu- and kappa-opiate receptors in the medial preoptic area (MPOA) of male and female rats across the estrous cycle was examined using quantitative in vitro autoradiography of [3H]D-Ala2,MePhe4,Gly-ol5-enkephalin (DAGO), [3H]naloxone and [3H]bremazocine binding. While no difference in kappa-receptor labeling was observed across sex or estrous stage, selective mu-receptor labeling with [3H]DAGO revealed a significant variation of density and distribution in the MPOA across the estrous cycle and between sexes. A dense concentration of mu-receptors located in the central, sexually dimorphic portion of the MPOA was observed during metestrus and diestrus in females, but not during proestrus nor in males. This region appeared to be the same as that labeled similarly using [3H]naloxone. These results suggest that a regional substrate for functional activation by endogenous opioid peptides (e.g. beta-endorphin) is cyclically regulated in females, which may explain the gonadal steroid-dependent effects of MPOA beta-endorphin on lordosis and luteinizing hormone secretion in females.
Male rough-skinned newts (Taricha granulosa) were used as a model for the study of the neuroendocrine regulation of locomotion. Intracerebroventricular (i.c.v.) injections of nanogram quantities of corticotropin-releasing factor (CRF) dose-dependently increased locomotion as measured in a circular open-field test arena. In other studies animals received intraperitoneal (i.p.) injections of saline or naloxone, a synthetic opioid antagonist, followed by i.c.v. injections of saline or CRF. With 1-min intervals between injections, neither i.p. saline nor naloxone injections modified the stimulatory effects of CRF injections on locomotor activity. In contrast, with 20-min intervals between injections, the naloxone-plus-CRF injected newts displayed more locomotor activity than the saline-plus-CRF injected newts, suggesting that the opioid system modulated the behavioral effects of CRF. An i.p. injection of bremazocine, an opiate kappa-receptor agonist, suppressed spontaneous locomotion but not CRF-induced locomotion. In contrast, an i.p. injection of morphine, an opiate mu-receptor agonist, did not affect spontaneous locomotion but reduced CRF-induced locomotion, indicating further that the opioid system may modulate the behavioral effects of CRF in this amphibian. The present study provides the first evidence that both CRF and opioids may be involved in the regulation of amphibian locomotor activity.
The neuroanatomical localization of kappa opioid receptors in rat and guinea pig brain was determined by quantitative in vitro receptor autoradiography. Our study shows striking differences in kappa 1 and kappa 2 receptor distributions both between species and within each species. In the rat brain, kappa 1 sites (labeled by [3H]U-69,593) are of low density and confined to a small number of structures. These include the claustrum, endopiriform nucleus, caudate putamen, nucleus accumbens, midline nuclear group of the thalamus, superficial grey layer of the superior colliculus, and central grey. kappa 2 sites (labeled by [3H]ethylketocyclazocine or [3H]bremazocine under conditions in which mu, delta, and kappa 1 binding was suppressed) are more widely distributed throughout all levels of rat brain. kappa 2 sites occur at high density in the caudate putamen, nucleus accumbens, amygdala, thalamus, and interpeduncular nuclei. In guinea pig brain, kappa 1 sites predominate and are of high density in layers I and VI of the neocortex, claustrum, endopiriform nucleus, caudate putamen, nucleus accumbens, and molecular layer of the cerebellum. As in rat brain, kappa 2 sites in guinea pig are more uniformly and widely distributed throughout the brain than are kappa 1 sites. The highest density of kappa 2 sites is in the dorsal parabrachial nucleus, interpeduncular nuclei, mammillary nuclei, and posterior thalamic nuclei. Results from this study demonstrate important interspecies differences in the distribution of kappa 1 and kappa 2 opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
beta-Endorphin, met-enkephalin and several mu-selective opioid agonists were shown to decrease thymidine incorporation into DNA in various neural cell cultures. We now report that the kappa-selective opioid agonists U50488, U69593 and MR2034 modulate [3H]thymidine incorporation into DNA in rat spinal cord-dorsal root ganglion co-cultures. U50488 at 10 microM increased by 60% thymidine incorporation in 6-day-old cultures. The thymidine incorporation induced by U50488 was blocked by the kappa-selective antagonist nor-binaltorphimine, as well as by pertussis toxin and LiCl. U50488 treatment stimulated phosphatidylinositol turnover by three-fold compared with untreated controls. These findings suggest that kappa-opioid agonists modulate DNA synthesis in spinal cord-dorsal root ganglion co-cultures through a mechanism which involves pertussis toxin-sensitive GTP-binding proteins, as well as activation of phosphatidylinositol turnover.
In an attempt to determine the opioid receptor class(es) which underly the two opposing effects of naloxone in models of persistent pain, we tested the action of the selective delta antagonist naltrindole, and that of the kappa antagonist MR-2266 on the bidirectional effect of systemic naloxone in arthritic rats. As a nociceptive test, we used the measure of the vocalization thresholds to paw pressure. The antagonists were administered at a dose (1 mg/kg i.v. naltrindole, 0.2 mg/kg i.v. MR-2266), without action per se but which prevents the analgesic effect of the delta agonist DTLET (3 mg/kg, i.v.) or the kappa agonist U-69,593 (1.5 mg/kg, i.v.) respectively, and does not influence the effect of morphine (1 mg/kg i.v.) or the mu agonist DAMGO (2 mg/kg, i.v.) in these animals. In arthritic rats injected with the delta antagonist, the paradoxical antinociceptive effect produced by 3 micrograms/kg i.v. naloxone was not significantly modified (maximal vocalization thresholds (% of control) were 146 +/- 9% versus 161 +/- 7% in the control group). By contrast, the hyperalgesic effect produced by 1 mg/kg i.v. naloxone was significantly reduced (maximal vocalization thresholds were 87 +/- 4% versus 69 +/- 5% in the control group). In rats injected with the kappa antagonist, the antinociceptive effect of the low dose of naloxone was almost abolished (mean vocalization thresholds were 115 +/- 3% versus 169 +/- 7%) whereas the hyperalgesic effect of naloxone 1 mg/kg i.v. was not significantly modified (mean vocalization thresholds = 70 +/- 3% and 65 +/- 3%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
The role of brain delta- and kappa-opioid receptors in the regulation of PFC response, Arthus hypersensitivity reactions and delayed hypersensitivity reactions was studied following intracerebroventricular (i.c.v.) administration of opioid receptor agonists and antagonists. Eight-week-old male Wistar rats, with polyethylene cannulae inserted into the lateral brain ventricles, were i.c.v. treated with different doses of delta-opioid receptor agonist methionine-enkephalin (Met-Enk), delta-opioid receptor antagonist ICI 174864, kappa-opioid receptor agonist MR 2034, and kappa-opioid receptor antagonist MR 2266. In rats sensitized for plaque-forming cell (PFC) assay, the first drug injection was given 1 h prior to immunization, and then every 24 h until day 4. One h after the last treatment, rats were sacrificed and (PFC) assay performed. In rats immunized for hypersensitivity skin reactions, the first drug injection was given 1 h before immunization, and then every 48 h until day 14. Skin reactions were elicited one h after the last drug administration. Opioid receptor agonists Met-Enk and MR 2034 stimulated and suppressed PFC response, Arthus and delayed skin reactions respectively. ICI 174864 decreased the number of PFC and intensity of hypersensitivity skin reactions whereas MR 2266 increased the number of PFC, but did not affect to a greater extent hypersensitivity reactions. Stimulation of PFC produced by 1 microgram/kg of Met-Enk was completely blocked with 10 and 50 micrograms/kg of ICI 174864. MR 2034-induced suppression was partially and completely antagonized with 10 and 50 micrograms/kg of MR 2266 respectively. The present results suggest that brain opioid receptors differentially affect humoral and cell-mediated immune responses.
It was previously observed that chronic food restriction lowers the threshold for lateral hypothalamic self-stimulation in a manner that is reversible by mu- and kappa-selective opioid antagonists. The present quantitative autoradiographic study was designed to investigate whether chronic food restriction alters regional mu and kappa opioid binding in brain. [3H]DAGO (mu) and mu/delta blocked [3H]BMZ (kappa) binding were analyzed in 34 brain regions from the medial prefrontal cortex to posterior hypothalamus. Significant reductions in mu binding were observed in caudal portions of the medial and lateral habenula, and the basolateral and basomedial nuclei of the amygdala. kappa binding was similarly reduced in medial habenula. Large increases in kappa binding were observed in the bed nucleus of the stria terminalis, ventral pallidum, and medial preoptic area. The possible involvement of these changes in the sensitization of reward by food restriction is discussed.