Cold-water Swim Analgesia Research Articles

Antagonism of morphine analgesia by nonopioid cold-water swim analgesia: Direct evidence for collateral inhibition

The demonstrated existence of opioid and nonopioid forms of pain control has raised questions as to how they interact. Previous indirect evidence suggests that activation of one system inhibited the activation of the other. The present study assessed this directly using morphine as an opiate form of analgesia and continuous cold-water swims (CCWS, 4 degrees C, 2 min) as the nonopioid form. A significant reduction in morphine (8 mg/kg, SC) analgesia on the tail-flick test was observed if rats were acutely exposed to CCWS immediately prior to morphine administration. The inability of naloxone (10 mg/kg, SC) to reduce CCWS analgesia verified its nonopioid nature. The antagonism of morphine (3 mg/kg, SC) analgesia was greater following preexposure to 2 min of CCWS than 1 min of CCWS. CCWS was also more effective in antagonizing analgesia induced by the 3 mg/kg than the 8 mg/kg dose of morphine. The antagonism of morphine analgesia by CCWS was dependent upon the temporal patterning of stimulus presentation: exposure to CCWS 20 or 60 min prior to morphine failed to alter subsequent morphine analgesia. A significant reduction in analgesia induced by intraperitoneal administration of morphine (10 mg/kg) was also observed when CCWS was presented immediately prior to injection, suggesting that pharmacokinetic factors such as altered drug absorbance by CCWS-induced vasoconstriction do not appear to explain these effects. These data provide direct support for the existence of collateral inhibitory mechanisms activated by CCWS and morphine, and suggests that these opioid and nonopioid forms of analgesia do not function synergistically, but instead involve some form of hierarchical order.

Analgesia induced by continuous versus intermittent cold water swim in the rat: Differential effects of intrathecal administration of phentolamine and methysergide

Continuous cold water swim produces analgesia that is partially mediated by a noradrenergic mechanism, but is independent of both serotonergic and opioid systems. On the other hand, intermittent cold water swim elicits analgesia which is partly mediated by an opioid mechanism; the contribution of the monoamines to the production of this analgesia is not known. Therefore, the present study was done to determine whether intermittent cold water swim is also mediated by noradrenergic and/or serotonergic substrates. Prior to either continuous (3.5 min) or intermittent (10 sec in, 10 sec out for 6 min) cold water (4°C) swim, male Sprague-Dawley rats (225–250 g) were administered either the noradrenergic receptor blocker phentolamine (30 μg), the serotonergic blocker methysergide (30 μg) or artificial cerebrospinal fluid to the fifth lumbar vertebral spinal level via chronic intrathecal catheters. Phentolamine significantly attenuated the analgesia resulting from both continuous and intermittent cold water swim. Methysergide attenuated intermittent cold water swim analgesia, but was without effect on continuous cold water swim analgesia. Phentolamine, but not methysergide, also attenuated continuous footshock-(2.5 mA for 3 min) induced analgesia. The similarity between the effects of phentolamine and methysergide on continuous footshock and continuous cold water swim analgesia suggests that the effects of these drugs on cold water swim analgesia are not attributable to changes in thermoregulation. These results suggest that a spinal noradrenergic mechanism is involved in the mediation of both forms of cold water swim analgesia, whereas a spinal serotonergic mechanism is involved in only intermittent cold water swim analgesia.

Lack of effect of adrenal denervation on analgesia elicited by continous and intermittent cold water swim in the rat

The present experiment was conducted to determine if continous and/or intermittent cold water swim analgesia is dependent upon a factor released from the adrenal medullae. Male Sprague-Dawley rats (300–350 g) underwent either bilateral adrenal denervation or sham surgery and two weeks later were exposed to continous (3.5 m) or intermettent (10 s in, 10 out for 6 min) swim in water at 4 °C. Adrenal denervation failed to affect either intermittent or continous cold water swim analgesia. It was concluded that both types of cold water swim analgesia are independent of adrenal medullary function.

Chronic opioid antagonist treatment facilitates nonopioid, stress-induced analgesia.

Chronic exposure to opioid antagonists produces increases brain opioid receptors and enhances morphine analgesia. Since opioid antagonists could affect both opioid and nonopioid analgesic systems, the present study evaluated whether chronic opioid antagonist treatment with naltrexone alters the nonopioid analgesia produced by cold-water swims (CWS). Rats were implanted (SC) with two, 30 mg naltrexone pellets. The pellets were removed 8 days later or left in place and rats tested 24 hr later for analgesia (tail-flick) following a 3.5 min CWS or morphine (3 mg/kg, SC). As expected, morphine analgesia was potentiated in rats with naltrexone pellets removed, but was blocked in rats tested with the naltrexone still implanted. In contrast, naltrexone pretreatment potentiated CWS analgesia, irrespective of whether the pellets were removed or left in place. These findings confirm the nonopioid nature of CWS analgesia and indicate that chronic treatment with an opioid antagonist can affect both opioid and nonopioid analgesic mechanisms.

Reduction in cold-water swim analgesia following hypothalamic paraventricular nucleus lesions

The analgesic response following cold-water swims (CWS) has been shown to be mediated through neurohormonal mechanisms and independently of opioid systems. The hypothalamic paraventricular nucleus (PVN) appears to be important in autonomic, hypophysial and medial-basal hypothalamic function. The present study examined whether lesions placed in the PVN in rats would alter CWS analgesia on the tail-flick test. Animals with lesions placed in the PVN displayed significant reductions in analgesic magnitude 30 (66%) and 60 (54%) min following CWS relative to sham-treated rats without alterations in baseline latencies. In contrast, CWS analgesia was not altered in animals with lesions placed dorsal and/or lateral to the PVN. These data are discussed in terms of the roles of PVN projections to the median eminence and brainstem/spinal structures as well as roles for neurpopeptides in the PVN.

Gender differences in two forms of cold-water swim analgesia

Female rats display lower shock thresholds and less morphine analgesia than male rats, differences which are sensitive to gonadal manipulations. Baseline pain thresholds and morphine analgesia also vary across the estrous cycle of female rats. The first experiment demonstrated that 'nonopioid' continuous cold-water swim (CCWS: 2 degrees C for 3.5 min) analgesia and 'opioid' intermittent cold-water swim (ICWS: 2 degrees C, 18 10-sec swims and 10-sec rests over 3 min) analgesia are subject to gender-specific effects. The magnitudes of CCWS and ICWS analgesia were significantly lower in female rats as compared to either age-matched or weight-matched male rats. The jump test displayed a more consistent pattern than the tail-flick test. The second experiment failed to show differences in the magnitude of CCWS analgesia across the female estrous cycle. These data demonstrate that both opioid (ICWS) and nonopioid (CCWS) forms of stress-induced analgesia are sensitive to gender differences, and suggest that male gonadal hormones may enhance analgesic responsivity.

Age-related decrements in the analgesic response to cold-water swims

Among the compromised physiological responses affected by aging is an impaired ability to thermoregulate in a cold environment. Since acute exposure to cold-water swims (CWS) produces both analgesic and hypothermic responses in young adult rats, the present study examined whether systematic variations in these responses occurred as a function of age. Separate cohorts of 4, 9, 14, 19 and 24-month old female rats received a no-swim condition and a 2°C swim for 3.5 min with tail-flick latencies, jump thresholds and core body temperature assessed 30, 60 and 90 min later. The order of conditions was counterbalanced with an interval of four days between conditions. While the four younger cohorts displayed similar CWS analgesia on the tail-flick test, the 24-month cohort failed to display CWS analgesia on this measure. Age-related differences in CWS analgesia on the jump test appeared more gradual with the three older cohorts displaying significant attenuations relative to the 9-month group, and the oldest cohort displaying significant attenuations relative to the 4-month group. In contrast, the hypothermic effect of CWS was significantly potentiated in the three oldest cohorts, with a progressive inability to cope with thermoregulation observed as a function of age. The observed decrements in the analgesic response to CWS as a function of age appear to represent a change in (a) the ability of the animal to perceive the CWS stimulus as stressful (b) an endogenous pain-inhibitory system and/or (c) an endogenous pain transmission system that is independent of thermoregulatory mechanisms.

Gender differences in two forms of cold-water swim analgesia

Gender differences in two forms of cold-water swim analgesia

Potentiation of cold-water swim analgesia by acute, but not chronic desipramine administration

Like other stress responses, cold-water swim (CWS) analgesia can be altered by changes in norepinephrine (NE) availability. While clonidine pretreatment potentiates CWS analgesia, lesions placed in the noradrenergic locus coeruleus reduce this response. Desipramine (DMI) can alter both the availability and receptor function of catecholamines, particularly NE: while both acute and chronic DMI treatments decrease NE reuptake, subsensitivity of beta-adrenergic receptors occurs only after chronic DMI treatment. The present study examined whether acute and chronic DMI treatments differentially alter CWS analgesia as measured by the jump test. CWS hypothermia and basal jump thresholds. The first experiment determined that pretreatment at either 24, 5 and 1 hr or only at 1 hr with DMI doses of 20 and 5 but not 1 mg/kg potentiated CWS analgesia. The second experiment found that chronic DMI pretreatment at a dose of 10 mg/kg administered twice daily over seven days failed to alter CWS analgesia at 1, 24, 48 or 72 hr thereafter. Neither CWS hypothermia nor basal jump thresholds were affected by the acute or chronic DMI injection regimens. The selective potentiation of CWS analgesia by acute DMI pretreatment is discussed in terms of the differential actions of acute and chronic injection regimens upon NE availability, receptor function, and adaptation processes.

Reduction in cervical probing analgesia by repeated prior exposure to cold-water swims

Previous work has established that stimulation of the vaginal cervix (cervical probing: CP) and cold-water swims (CWS) each produce analgesia in rats that is affected similarly by catecholaminergic mechanisms, but differentially by serotoninergic and opioid mechanisms. The present study examined whether CP analgesia, like CWS analgesia, would be reduced by prior repeated CWS exposure. Tail-flick latencies were significantly increased by CP and CWS in naive animals. In animals chronically preexposed to 14 daily swims, CP analgesia was reduced and CWS analgesia was reduced at 60, but not 30 min after the swim. After 1 month of recovery, CP analgesia showed a persistent reduction, whereas CWS analgesia was fully recovered. These data suggest that the mechanisms. underlying CP and CWS analgesia are interrelated.

Potentiation of cold-water swim analgesia and hypothermia by clonidine

The analgesia induced by acute exposure to cold- water swims (CWS) covaries with levels of brain norepinephrine and is reduced by lesions placed in the locus coeruleus. In assessing whether alpha-noradrenergic receptor mechanisms mediated CWS analgesia, the first experiment found that clonidine pretreatment (500, 1000 μg/kg) elevated jump thresholds 60 min following injection. While clonidine (1000 μg/kg) paired with a 2°C CWS potentiated CWS analgesia in a synergistic manner, additivity of analgesic effects was observed following pairing of clonidine (500 μg/kg) with a 2°C CWS and pairing of clonidine (500 and 1000 μ/kg) with a 15°C CWS. The second experiment showed that clonidine (500 μg/kg) paired with a 2°C CWS enhanced CWS analgesia on the tail-flick test. The third experiment indicated that while clonidine (500 and 1000 μg/kg) or CWS (2°C) each produced hypothermia, pairing of these clonidine doses with CWS enhanced CWS hypothermia. These data are discussed in terms of the possible modulatory role that norepinephrine, and particularly its alpha-noradrenergic receptor subclass, plays in the full expression of CWS analgesia and hypothermia.

Naloxone and cold-water swim analgesia: Parametric considerations and individual differences

The role of endogenous opioids in the mediation of stress-induced analgesia has been studied using the opiate antagonist naloxone to reduce or eliminate the response. While the analgesic responses following some stressors are reduced by naloxone, other stressors, like cold-water swims, are altered minimally. However, in the case of inescapable foot shock analgesia, the temporal, numerical, and spatial arrangement of the shocks are critical parameters in determining whether naloxone is capable of altering the analgesic state. In assessing parametric variations of naloxone antagonism of cold-water swim analgesia, five experiments were performed. The first experiment showed that naloxone antagonized the analgesic response following a 3.5-min swim in a 15°C bath, but not in baths of 8°C and 2°C. The second experiment demonstrated dose-dependent antagonism of analgesia induced by 2°C swims for 2.5 and 3.5 min; shorter durations failed to increase thresholds. The third experiment indicated that naloxone decreased 2°C, 3.5-min swim analgesia when the pain test occurred 30 min after stress; longer intervals failed to produce analgesia. The fourth experiment showed that the temporal relationship between injections and swims had little bearing on resultant effects. Finally, since it appeared that naloxone decreased analgesia induced by the 2°C, 3.5-min swim in some animals, but not others, the fifth experiment found that the degree of naloxone antagonism was correlated with the magnitude of the analgesic response induced in individual animals. These results are discussed in terms of opioid and nonopioid mechanisms subserving pain inhibition.

Capsaicin treatment and stress-induced analgesia

Capsaicin modulates animal pain perception, increasing chemosensitive and pressure thresholds following systemic administration, increasing thermal thresholds following intrathecal administration, and decreasing electric shock thresholds following intracerebroventicular (ICV) administration. Since morphine analgesia is decreased in a dose-dependent manner following ICV capsaicin, the present study examined whether ICV injections of capsaicin (0, 25, 50, 100 μg) would alter other analgesic responses as well. Experiment 1 demonstrated that the analgesic response to a 450 mg/kg dose of 2-deoxy-D-glucose was significantly reduced by the 25 and 50, but not the 100 μg capsaicin dose. Further, while analgesia induced by cold-water swims (CWS) in a 2°C bath was significantly attenuated by the 25 μg capsaicin dose, the entire dose range eliminated analgesia induced by CWS in a 15°C bath. Experiment 2 indicated that the capsaicin-induced alterations in CWS analgesia were not attributable to parallel changes in CWS hypothermia. Experiment 3 demonstrated that capsaicin failed to alter both the non-opioid analgesic response induced by 20 inescapable foot shocks (FS) and the opioid analgesic response induced by 80 FS. These data are discussed in terms of the similarities to and/or dissimilarities from capsaicin-induced effects upon morphine analgesia.

Naloxazone and pain-inhibitory systems: evidence for a collateral inhibition model.

The analgesic responses following morphine and cold-water swims (CWS) can be dissociated from each other. Indeed, certain manipulations in rats such as hypophysectomy or D-phenylalanine injections decrease CWS analgesia while increasing morphine analgesia. The present study examined the reciprocal notion, namely whether a manipulation that decreases morphine analgesia would increase CWS analgesia. Naloxazone, an opiate antagonist which selectively inhibits the high affinity binding site in a long-acting manner, was administered intracerebroventricularly and assessed for its effects upon morphine analgesia and CWS analgesia as measured by the jump test. While intracerebroventricular injections of naloxazone reduced morphine analgesia at 0.5 and 24 hr following microinjection, the same 50 micrograms dose significantly increased CWS analgesia at 0.5 hr after injection, suggesting a mechanism of collateral inhibition between opioid and non-opioid pain-inhibitory systems.

Analgesic responses following adrenal demedullation and peripheral catecholamine depletion

Adrenalectomy affects analgesic responses differentially, potentiating morphine and cold-water swim analgesia while reducing prolonged, intermittent foot shock analgesia. Adrenocortical influences also exhibit differential effects: dexamethasone pretreatment potentiates morphine analgesia while reducing both forms of stress-induced analgesia. In assessing sympathomedullary influences in analgesic processes, adrenal demedullation reduces prolonged, intermittent foot shock analgesia. The present study examined the effects of adrenal demedullation both with (MADX/6-OHDA) and without (MADX) peripheral 6-hydroxydopamine injections upon the analgesic responses following 2°C and 15°C swims and following 5 mg/kg and 2.5 mg/kg doses of morphine. Significant reductions were observed in adrenal epinephrine levels in all MADX rats and in heart norepinephrine levels in MADX/6-OHDA rats. Despite the adrenal demedullation and sympathetic dennervation, neither the MADX group nor the MADX/6-OHDA group differed significantly from sham control rats in their baseline post-operative or post-injection flinch-jump thresholds, in their analgesic responses following the 2°C and 15°C swims, or in their analgesic responses following the 5 mg/kg and 2.5 mg/kg morphine doses. These data are assessed in terms of divergent adrenal influences upon various analgesic responses.

Cold-water swim analgesia following pharmacological manipulation of GABA

Since increased GABA binding is observed in mice following cold-water swims (CWS) that parallels the analgesic time course, this suggests that GABA availability may modulate CWS analgesia. To test this, separate groups of rats received either the GABA agonist muscimol (75, 150, 300 μ g/kg) or the GABA antagonist picrotoxin (0.25, 0.5, 1.0, 2.0 mg/kg) paired 30 min later with CWS. Neither muscimol nor the three lower picrotoxin doses significantly altered CWS analgesia or jump thresholds per se as compared to saline-treated rats. While the 2-mg/kg-picrotoxin dose potentiated CWS analgesia, it also produced convulsive activity which in itself is analgesic. These data suggest that the observed changes in GABA following CWS may not constitute necessary and sufficient conditions to explain CWS analgesia.

Antagonism of stress-induced analgesia by D-phenylalanine, an anti-enkephalinase.

Methionine- and leucine-enkephalin produce mild and transient analgesic effects, presumably because of enzymatic degradation. Administration of high (250 mg/kg) doses of D-phenylalanine retards the degradation process and elicits analgesia which is reversed by naloxone and which summates with electroacupuncture analgesia. The present study evaluated D-phenylalanine's dose-dependent effects upon a non-opioid analgesic treatment, cold-water swims (CWS), and compared this with morphine. following determination of flinch-jump baselines, three groups of rats received respectively either 25, 50 or 100 mg/kg of D-phenylalanine intraperitoneally in three conditions: alone, with CWS (2 degrees C for 3.5 min), and with morphine (5 mg/kg, SC). Parallel controls with saline were also tested. Simultaneous exposure with each minimally analgesic dose of D-phenylalanine reduced significantly the analgesic, but not hypothermic effects of CWS. By contrast, morphine analgesia was unaffected by D-phenylalanine. These data provide further support that different pain-inhibitory systems mediate CWS and morphine analgesia and suggest that activation of one system is capable of exerting collateral inhibition upon the other.

Reversal of stress-induced analgesia by apomorphine, but not by amphetamine

Acute exposure to severe stressors induce profound analgesia as well as depleting catecholamine levels. The present study examined whether d-amphetamine and apomorphine, agents which increase catecholamine availability, would alter the analgesic effectiveness of cold-water swims (CWS) and 2-deoxy-D-glucose (2-DG) as measured by an operant liminal escape procedure. Two groups of 10 rats each were tested to determine alterations in liminal escape threshold functions following amphetamine at doses of 0.25, 0.5, 1,2 mg/kg and following apomorphine at doses of 0.025, 0.05, 0.1, 0.2 mg/kg. Half of the amphetamine and half of the apomorphine groups were tested across their respective dose ranges for the drug effects upon CWS analgesia. The remaining animals in each group received 2-DG (600 mg/kg IP) alone followed by 2-DG paired with each stimulant dose. No dose of amphetamine or apomorphine alone altered escape thresholds. While amphetamine produced slight potentiations of 2-DG analgesia at the two low doses, apomorphine at the 0.05 and 0.1 mg/kg doses returned CWS and 2-DG analgesia to within normal placebo values. These results provide indirect evidence for a role for brain norepinephrine and dopamine in stress-induced analgesia, and these data are discussed with respect to catecholamine involvement in pain-inhibitory processes.