Stress-induced Antinociception Research Articles

Effect of delayed weaning on opioid receptor control of swim stress-induced antinociception in the developing rat.

1. The opioid type of swim-stress induced antinociception (SIA) is mediated via mu-sites in preweanling rats and predominantly by delta-sites in postweanling animals. We have studied the effect of delay of weaning on the receptor transition of this behaviour in the developing rat. 2. Litters were weaned normally at day 21 or allowed to remain with their mothers until assessment of swim SIA. Animals were stressed by warm water (20 degrees C) swimming for 3 min periods and antinociception assessed by the tail immersion test (50 degrees C). 3. Naloxone (10 mg kg-1) partially reversed swim SIA in both 25 day old weaned and non-weaned rats. 4. Naltrindole (1 mg kg-1) partially reversed swim SIA in 25 day old weaned rats but had no effect in non-weaned animals. Naltrindole (5 mg kg-1) completely abolished swim SIA in weaned rats but was without effect in non-weaned groups. Antinociceptive responses to the mu-agonist, alfentanil (60 micrograms kg-1) were unaffected by naltrindole at 1 mg kg-1 but were partially reversed at 5 mg kg-1. 5. In 30 day old non-weaned rats, naltrindole (5 mg kg-1) abolished the swim SIA. 6. In conclusion, transition from mu to delta-receptor control of swim SIA in rat pups can be delayed by between 5 and 10 days by delay of weaning. The environmental stimulus of weaning can activate opioid receptor subtype operation of biological responses in the developing animal.

A method for the study of swimming stress and stress-induced antinociception in preweanling rats

Stress-induced antinociception (SIA) which is well characterized in the adult rat can also be observed in young rats, and, by varying swimming times, it can be dissociated into opioid and nonopioid forms. However, swimming ability in the rat does not fully develop until the third postnatal week and this has precluded the study of swim SIA in neonates. We report here the development of a harness device to aid swimming in young rats which we have successfully employed down to the age of 2 days without distress to the animals. Further we have also shown the development of the opioid form of swim SIA in the rat using this device. Swim SIA is absent at days 2 and 5, but at postnatal day 10 a small level of SIA is evident which is reversed by naloxone (10 mg/kg). Swim SIA develops rapidly thereafter, and the adult profile is observed by day 25.

Characterization of pituitary mediation of stress-induced antinociception in rats

Antinociception, induced by continuous cold-water swims (CCWS) and certain parameters of inescapable foot shock, is reduced in hypophysectomized rats receiving supplements of corticosterone and l-thyroxine. To assess which lobe of the pituitary gland is involved in this effect, the first experiment compared the effects of total hypophysectomy and posterior lobectomy in supplemented rats upon CCWS antinociception on the tail-flick and jump tests and upon continuous inescapable foot shock antinociception on the tail-flick test. Total hypophysectomy, but not posterior lobectomy, significantly reduced CCWS antinociception on both tests in supplemented rats relative to sham surgery. Both total and posterior hypophysectomy either reduced or potentiated foot shock antinociception as functions of shock intensity or duration of exposure in supplemented rats. To assess whether hormonal supplementation is necessary for the observed effects, the second experiment examined CCWS antinociception in sham-operated and hypophysectomized rats that received either no hormonal supplements or corticosterone andor l-thyroxine. These regimens failed to alter CCWS antinociception in sham-operated rats. Treatment of hypophysectomized rats with corticosterone and l-thyroxine either separately or together significantly reduced CCWS antinociception. In contrast, if hypophysectomized rats did not receive supplements, CCWS antinociception was significantly potentiated relative to sham-operated controls. These effects could not be attributed to treatment-induced changes in either body weight or CCWS hypothermia. These data suggest that the anterior lobe of the pituitary gland and adrenal cortex are involved in the mediation and/or maintenance of CCWS antinociception.

P-466 - Delta opioid receptor-mediated swimming stress-induced antinociception in the formalin test.

P-466 - Delta opioid receptor-mediated swimming stress-induced antinociception in the formalin test.

Antinociceptive and thermoregulatory actions of vasopressin are sensitive to a V 1-receptor antagonist

The involvement of arginine vasopressin (AVP) has been investigated in cold water swim (CWS) stress-induced antinociception (SIA) and CWS-induced hypothermia. The antinociceptive action of AVP (0.5 μg, i.c.v.) pre-CWS was antagonized by d(CH 2) 5Tyr(Me)AVP (0.5 μg, i.c.v.) but not by naloxone (5 μg, i.c.v.). CWS produced SIA on the hot-plate which was initially naloxone-insensitive. Neither AVP nor its antagonist had any significant effect on CWS SIA. AVP-induced increase in body temperature, during recovery from CWS-induced hypothermia, was significantly (P < 0.001) reduced in the presence of its antagonist. These findings suggest that the antinociceptive and thermoregulatory actions of AVP may be mediated via V 1-receptors.

Gene expression and localization of opioid peptides in immune cells of inflamed tissue: Functional role in antinociception

Our previous studies indicate that endogenous opioids (primarily β-endorphin) released during stressful stimuli can interact with peripheral opioid receptors to inhibit nociception in inflamed tissue of rats. This study sought to localize opioid precursor mRNAs and opioid peptides deriving therefrom in inflamed tissue, identify opioid containing cells and demonstrate their functional significance in the inhibition of nociception. In rats with Freund's adjuvant-induced unilateral hindpaw inflammation we show that: (i) pro-opiomelanocortin and proenkephalin-mRNAs (but not prodynorphin mRNA) are abundant in cells of inflamed, but absent in non-inflamed tissue; (ii) numerous cells infiltrating the inflamed subcutaneous tissue are stained intensely with β-endorphin and [Metjenkephalin (but only few scattered cells with dynorphin) antibodies; (iii) β-endorphin is present in T- and B-lymphocytes, monocytes and macrophages; and (iv) whole-body irradiation suppresses stress-induced antinociception in the inflamed paw. Taken together, these data suggest that endogenous opioid peptides are synthesized and processed within various types of immune cells at the site of inflammation. Immunosuppression abolishes the intrinsic antinociception in inflammatory tissue confirming the functional significance of these cells.

Involvement of histamine in naloxone-resistant and naloxone-sensitive models of swim stress-induced antinociception in the mouse

The antinociceptive activity of histamine in male mice has been demonstrated using chemical and thermal noxious stimuli and its involvement in naloxone-sensitive and naloxone-insensitive models of stress-induced antinociception investigated. In the abdominal constriction test, histamine and dimaprit but not histidine, induced antinociception. Compound 48/80 and H 1 antagonists (diphenhydramine, mepyramine and promethazine) and large doses of H 2 antagonists (cimetidine and zolantidine) produced antinociception in this test. Antinociception induced by histamine was refractory to mepyramine, metiamide and naloxone. Histamine and non-antinociceptive doses of its antagonists had no influence on the naloxone-resistant warm water swim stress-induced antinociception. In the hot-plate test, histamine agonists, except the H 3 agonist (R)α-methyl histamine (α-MeHA), were antinociceptive but all these agents augmented the naloxone-sensitive room temperature swim stress-induced antinociception, after either intraperitoneal or intraventricular injection. The antinociceptive action of dimaprit was not antagonized by zolantidine which, like other histamine antagonists excluding metiamide, also produced antinociception and enhanced room temperature swim stress-induced antinociception. These findings suggest that histamine is involved in pathways mediating antinociception in the mouse and that such pathways are activated in a naloxone-sensitive model of stress-induced antinociception but not in a naloxone-insensitive model.

Peripheral opioid receptors mediating antinociception in inflammation. Activation by endogenous opioids and role of the pituitary-adrenal axis

This study investigated the involvement of endogenous opioid peptides in mediating cold water swim (CWS) stress-induced antinociception (SIA) in rats with unilateral hind paw inflammation induced by Freund's complete adjuvant (FCA). Following 0.5, 1 and 2 min of CWS, there was a duration-dependent elevation of paw pressure threshold (PPT) in both inflamed and non-inflamed paws which was maximal immediately after CWS and returned to control values within 15 min. The antinociception elicited in the inflamed paw was significantly greater than that elicited in the non-inflamed paw. The antinociception induced by a 1 min CWS was dose dependently antagonized by tertiary naloxone (0.125–1 mg/kg s.c.) and completely reversed by tertiary naltrexone (0.5 mg/kg). Quaternary naltrexone (5–40 mg/kg s.c.) was similarly effective in reversing the elevation of inflamed PPT induced by a 1 min CWS stress. In contrast, similar doses of quaternary naltrexone had no effect against centrally mediated morphine antinociception in non-inoculated rats. Adrenalectomy was without effect on the pattern of SIA seen in FCA-treated rats. Surgical hypophysectomy completely abolished the differential antinociception induced by 0.5 and l min durations of CWS but had little effect on that following 2 min of CWS stress. Inhibition of hypophysial corticotrophic cell secretion with dexamethasone (300 μg/kg) injected s.c. 120 min prior to CWS completely abolished the differential SIA at all durations of CWS tested. β-Endorphin 12.5 μg/kg administered i.v. in non-stressed rats also caused a greater elevation of PPT in inflamed than in non-inflamed paws. This effect was not reversed by concomitant i.v. administration of (−) tertiary naloxone 5 mg/kg or quaternary naltrexone 20 mg/kg.

The ontogeny of thermal nociception in domestic fowl: Thermal stimulus intensity and isolation effects

Socially housed leghorn cockerels were confined to a heated grid (55, 57, or 59 degrees C, Experiment 1; 59, 61, or 63 degrees C, Experiment 2) and tested at posthatch ages of 14 days (Experiment 1) and 1, 3, 7, or 14 days (Experiment 2). In Experiment 1, chicks performed a discrete jump response only at 59 degrees C. In Experiment 2, jump latency was inversely related to temperature at each age but significantly so only at 7 and 14 days posthatch. At the highest temperature, jump latency did not differ significantly across ages. At medium and low temperatures, latency increased from 1 and 3 to 7 days posthatch (antinociceptive effect) and decreased thereafter. Chicks raised in isolation from hatch to 7 days posthatch (Experiment 3) did not display the increased jump latency (antinociceptive effect) displayed by socially raised chicks. Developmental increases in jump latency may reflect stress-induced antinociceptive concomitants of neophobia that emerge with age in this precocial species and social experience may be required for the normal development of this stress-induced antinociception.

Vasopressin and stress‐induced antinociception in the mouse

1. Arginine vasopressin produced antinociception in the hot-plate test after intracerebroventricular injection (0.5 micrograms) and in the acetic acid abdominal constriction test after intraperitoneal injection (0.1 mg kg-1). 2. The antinociception produced by arginine vasopressin was sensitive to deamino(CH2)5Tyr(Me) arginine vasopressin (0.5 micrograms i.c.v.; 0.1 mg kg-1 i.p.) but not to naloxone (5 micrograms i.c.v.; 2 mg kg-1 i.p.) 3. Arginine vasopressin when administered by the intracerebroventricular route, but not by the intraperitoneal route, produced characteristic behaviour which was sensitive to deamino(CH2)5Tyr(Me) arginine vasopressin (0.5 micrograms, i.c.v.). 4. A 3 min swim at 20 degrees C produced antinociception on the hot-plate which was sensitive to naloxone (0.4 mg kg-1, i.p.) but not to deamino(CH2)5Tyr(Me) arginine vasopressin (0.5 micrograms, i.c.v.). 5. The reduction in the number of acetic acid-induced abdominal constrictions produced by a 30 s swim at 30 degrees C was not sensitive to either naloxone (2 mg kg-1, i.p.) or deamino(CH2)5Tyr(Me) arginine vasopressin (0.1 mg kg-1, i.p.). 6. Arginine vasopressin, at high doses, is antinociceptive in the mouse but does not appear to mediate stress-induced antinociception in this species.

Exploring δ-receptor function using the selective opioid antagonist naltrindole

Until recently the only pharmacological probes for δ-receptors have been peptide enkephalin analogues. These suffer from a number of limitations including high cost, partial agonist effects and a propensity for neurotoxicity. A stable non-peptide antagonist, naltrindole, has recently become available. We have explored its intrinsic actions and found that it attenuated swim stress-induced antinociception, a model for endogenous δ-receptor activation. Naltrindole may therefore be a useful alternative to presently available δ-receptor antagonists.

Perinatal lead exposure impairs opioid but not non‐opioid stress‐induced antinociception in developing rats

1. The development of opioid systems has been shown to be sensitive to perinatal exposure to lead. We have studied the effects of such exposure on opioid and non-opioid mediated stress-induced antinociception in developing rats. 2. Lead was administered in the maternal drinking water from conception to postnatal day 14 at 300 and 1000 p.p.m. Twenty and 25 day old rats were subjected to swimming stress and antinociception measured using the tail immersion test. 3. A 3 min swim-stress induced an opioid-mediated antinociceptive response in 20 day old rats which was attenuated by 300 p.p.m. lead and by 1000 p.p.m. lead treatment in a dose-related manner. A 10 min swim-stress induced a non-opioid mediated antinociceptive response in 25 day old rats which was not antagonised by 300 or 1000 p.p.m. lead. 4. Naloxone antagonised the residual antinociception observed in 20 day old animals treated with 300 p.p.m. lead and had no effect on antinociception in control or lead-treated 25 day old rats. 5. Using a lead exposure model considered to represent subclinical lead toxicity in man, it was shown that perinatal lead exposure disrupts opioid but not non-opioid mediated stress antinociception.

Autotomy behavior in rats following peripheral deafferentation is suppressed by daily injections of amitriptyline, diazepam and saline

Amitriptyline, a tricyclic antidepressant (TCA), was effective in suppressing self-mutilation of a peripherally deafferented hind paw in rats (‘autotomy’). This effect was not due to the drug's sedative effect, since locomotor activity was not lower in treated than untreated rats. Daily injections of normal saline also suppressed autotomy, but for a shorter period of time than amitriptyline. This effect was not apparent in diazepam-treated rats, suggesting that the saline injection delayed autotomy as a result of stress-induced anti-nociception. Since amitriptyline is effective in humans in alleviating certain chronic pain disorders, these results further corroborate the suggestion that autotomy is a model of chronic pain, sensitive to centrally acting analgesics and to some forms of stress.

Swim-stress-induced antinociception in young rats.

1. Opioid and non-opioid mechanisms have been implicated in the phenomenon of stress-induced antinociception in adult rodents. We have studied stress-induced antinociception in developing rats and characterized differences in the neurochemical basis of this effect in pre- and post-weanling animals. 2. Twenty and 25 day old rats were stressed using warm water (20 degrees C) swimming for 3 or 10 min periods and antinociception was assessed by the tail immersion test (50 degrees C). 3. A 3 min swim in 20 and 25 day old rats produced marked antinociception which was blocked by naloxone, Mr 1452, 16-methyl cyprenorphine and levallorphan but not Mr 1453 or N-methyl levallorphan. The delta-opioid receptor antagonist ICI 174,864 attenuated stress-induced antinociception in 25 day old rats but was without effect in 20 day old animals. 4. A 10 min swim in 25 day old rats produced antinociception which was non-opioid in nature. In contrast, antinociception was not observed in 20 day old rats after a 10 min swim-stress. 5. Pretreatment of animals with dexamethasone blocked 3 min swim-stress antinociception in 20 and 25 day old animals but had no effect on antinociception induced by a 10 min swim. 6. Swim-stress-induced antinociception can be observed in young rats and dissociated into opioid and non-opioid types dependent on the duration of swimming stress. The non-opioid type appears to develop more slowly and cannot be observed in preweanling rats. The opioid type is a predominantly mu-receptor phenomenon in preweanling animals but delta-receptor components are observable in postweanling rats.

The effect of gonadectomy on antinociception induced in mice by swim stress

A 30 s swim in water at 30°C reduced the number of abdominal constrictions produced in mice by i.p. acetic acid. Naloxone antagonised this stress-induced antinociception in the female but not in the male. Orchidectomy altered neither the antinociception nor its insensitivity to naloxone antagonism. However, oophorectomy completely abolished the antinociception induced by the swim. These results suggest a sex difference in the involvement of the endogenous opioid system in swim stress-induced antinociception in mice.

The effects of selective opioid delta-receptor antagonists on stress-induced antinociception and plasma corticosterone levels in mice

Antinociception produced in mice by a 3 min swim was attenuated by ICI 174,864 and by low doses of naloxone indicating the involvement of both δ- and μ-receptors. The degree of antinociception was not related to plasma corticosterone (CS) levels measured 11 min after the swim. Naloxone affected CS levels in control mice and appeared to reduce the CS response to stress: ICI 154,129 and ICI 174,864 did not produce consistent effects on plasma CS levels.

Involvement of dopamine in the antinociceptive response to footshock.

The effects of drugs which alter dopaminergic function on footshock-induced antinociception were studied in the rat. Antinociception due to brief (30 s) footshock was inversely related to dopamine (DA). Thus, it was increased by the DA receptor antagonists pimozide and haloperidol and decreased by the specific D2 dopamine receptor agonist LY 141865, but not by the specific D1 agonist SKF 38393. Although pimozide increased the antinociceptive effect of 30-s shock, it decreased that of 30-min shock. It is suggested that DA may have physiological roles in stress-induced antinociception, and that these may differ according to the duration of stress.

The involvement of opioid δ-receptors in stress induced antinociception in mice

The selective opioid δ-receptor antagonist, IC 154,129, attenuated the antinociception, assessed by prolongation of reaction time on the hot-plate, of mice which had swum for 3 min at 20°C. This stress-induced antinociception was also sensitive to naloxone suggesting the involvement of both δ- and μ-receptors. A swim of 0.5 min at 30°C did not produce antinociception on the hot plate but the writhing response to i.p. acetic acid was blocked by a non-opioid mechanism.

Conditioned morphine tolerance in the rat: Absence of a compensatory response and cross-tolerance with stress.

In four separate experiments with rats as subjects, strong evidence was obtained that tolerance development to morphine analgesia occurs most rapidly when morphine delivery is paired with salient contextual cues. However, contextual cues previously paired with morphine did not elicit conditioned drug-compensatory responses when presented to nondrugged animals. These results were obtained by different analgesia assessments, with different drug-administration--analgesia-test latencies, and in environments differing with respect to stress level. Stress level did influence nociceptive response, as it was found that the combination of bright illumination, white noise, and a strong odor resulted in antinociception in the absence of drug. Moreover, rats that had a history of receiving morphine in this stressful context were tolerant to this stress-induced antinociception, but only when morphine was present in their systems. In the final two studies, this antinociception, which was cross-tolerant with morphine, was characterized with respect to naloxone reversibility and brain levels of met- and leu-enkephalin as determined by radioimmunoassay.

The role of neurotransmitters in stress-induced antinociception (SIA)

The role of the neurotransmitters, norepinephrine, dopamine and serotonin in stress-induced antinociception (SIA) was examined by altering neurochemical tone with appropriate pharmacological tools. Quipazine (15.0 mg/kg, IP) a serotonin agonist, increased the peak and duration of antinociception following stress and BC-105 (3.0 mg/kg, IP), a serotonin antagonist, blocked the increase of tail-flick latency following stress. Clonidine (0.1 mg/kg, SC) an α 2 agonist, markedly decreased SIA whereas phenoxybenzamine (2.5 mg/kg, IP), an α 1 antagonist, increased the peak and duration of SIA. When dopaminergic tone was increased with apomorphine (0.05 mg/kg, SC) the increase of tail-flick latency after stress was markedly attenuated whereas blockage of dopamine receptors with haloperidol (2.5 mg/kg, IP) increased the peak and duration of SIA. Alterations of serotonergic, but not noradrenergic or dopaminergic, tone had similar effects on increased latency in tail-flick test produced by brain stimulation produced analgesia (SPA), morphine and SIA. These data support the hypothesis that alterations in tail-flick latency involves a serotonergic system.