Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C (original) (raw)
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Signaling pathway of morphine induced acute thermal hyperalgesia in mice
PAIN, 2006
Systemic administration of morphine induced a hyperalgesic response in the hot plate test, at an extremely low dose (1-10 lg/kg). We have examined in vivo whether morphine, at an extremely low dose, induces acute central hypernociception following activation of the opioid receptor-mediated PLC/PKC inositol-lipid signaling pathway. The PLC inhibitor U73122 and the PKC blocker, calphostin C, dose dependently prevented the thermal hypernociception induced by morphine. This effect was also prevented by pretreatment with aODN against PLCb 3 at 2 nmol/mouse and PKCc at 2-3 nmol/mouse. Low dose morphine hyperalgesia was dose dependently reversed by selective NMDA antagonist MK801 and ketamine. This study demonstrates the presence of a nociceptive PLCb 3 /PKCc/NMDA pathway stimulated by low concentrations of morphine, through lOR 1 receptor, in mouse brain. This signaling pathway appears to play an opposing role in morphine analgesia. When mice were treated with a morphine analgesic dose (7 mg/kg), the downregulation of PLCb 3 or PKCc at the same aODN doses used for the prevention of the hyperalgesic effect induced, respectively, a 46% and 67% potentiation in analgesic response. Experimental and clinical studies suggest that opioid may activate pronociceptive systems, leading to pain hypersensitivity and short-term tolerance, a phenomenon encountered in postoperative pain management by acute opioid administration. The clinical management of pain by morphine may be revisited in light of the identification of the signaling molecules of the hyperalgesic pathway.
Endogenous morphine modulates acute thermonociception in mice
Journal of Neurochemistry, 2002
The endogenous synthesis of morphine has been clearly demonstrated throughout the phylogenesis of the nervous system of mammals and lower animals. Endogenous morphine, serving as either a neurotransmitter or neurohormone, has been demonstrated in the nervous system of both vertebrates and invertebrates. As one of the effects of exogenous morphine is the modulation of pain perception, we investigated the effects that the depletion of endogenous morphine had on nociceptive transmission. The immunoneutralization of endogenous morphine from brain extracellular spaces was obtained through the intracerebroventricular administration of af®nity puri®ed anti-morphine IgG to mice, which then underwent the hot plate test. Endogenous morphine immunoneutralization decreased thermal response latency and attenuated the anti-nociceptive effect of the mu selective agonist DAMGO in hot plate test suggesting that endogenous morphine is involved in pain modulation.
Pain, 1997
Nerve ligation injury in rats results in reduced nociceptive and non-nociceptive thresholds, similar to some aspects of clinical conditions of neuropathic pain. Since underlying mechanisms of hyperalgesia and allodynia may differ, the present study investigated the pharmacology of morphine and MK-801 in rats subjected to a tight ligation of the L5 and L6 nerve roots or to a sham-operation procedure. Response to acute nociception was measured by (a) withdrawal of a hindpaw from a radiant heat source, (b) withdrawal of the tail from a radiant heat source or (c) the latency to a rapid flick of the tail following immersion in water at different noxious temperatures. Mechanical thresholds were determined by measuring response threshold to probing the hindpaw with von Frey filaments. Nerve ligation produced a significant, stable and long-lasting decrease in threshold to mechanical stimulation (i.e., tactile allodynia) when compared to sham-operated controls. Standardization of the diameter of the filaments (to that of the largest filament) did not alter the response threshold in nerve-injured animals. Nerve ligation produced decreased response latency of the ipsilateral paw (i.e., hyperalgesia) when compared to that of sham-operated rats. Tail-flick latencies to thermal stimuli induced by water at constant temperatures (48°, 52°or 55°C) or by radiant heat were not significantly different between nerve-injured and sham-operated groups. At doses which were not behaviorally toxic, MK-801 had no effect on tactile allodynia. At these doses, MK-801 blocked decreased paw withdrawal latency to radiant heat in nerve-injured rats, but did not significantly elevate the response threshold of sham-operated rats. Systemic (i.p.) or intracerebroventricular (i.c.v.) doses of morphine previously shown to be antiallodynic in nerve-ligated rats did not affect the response to probing with von Frey filaments in sham-operated controls. Intrathecal (i.t.) morphine did not change paw withdrawal thresholds elicited by von Frey filaments of either nerve-ligated rats (as previously reported) or of sham-operated rats at doses maximally effective against thermal stimuli applied to the tail or foot. Spinal morphine produced dosedependent antinociception in both nerve-injured and sham-operated groups in the foot-flick test but was less potent in the nerve-injured group. Presuppression of hyperalgesia of the foot with i.t. MK-801 in nerve-injured animals did not alter the potency of i.t. morphine. I.t. morphine was also active in the tail-flick tests with decreased potency in nerve-injured animals and, at some stimulus intensities, with a decreased efficacy as well. These data emphasize the distinction between the inactivity of morphine to suppress mechanical withdrawal thresholds (as elicited by von Frey filaments) and the activity of this compound to block the response to an acute thermal nociceptive stimulus in sham-operated or nerve-injured rats. It appears that nerve ligation injury produces a thermal allodynia/hyperalgesia which is likely dependent upon opioid-sensitive small-diameter primary afferent fibers and a mechanical allodynia which may be largely independent of small-fiber input. © 1997 International Association for the Study of Pain. Published by Elsevier Science B.V.
General Pharmacology: The Vascular System, 1991
The effect of intraperitoneal injections of U-50,488H, a x-opiate receptor agonist, on the development of tolerance to the analgesic and hyperthermic effects of morphine was determined in male Sprague-Dawley rats. 2. Tolerance was induced by implantation of four morphine pellets during a 3-day period (4/3 schedule) or six morphine pellets during a 7-day period (6/7 schedule). 3. Administration of U-50,488H (25 mg/kg, twice a day for 3 days in 4/3 schedule) or (5, 10 and 20 mg/kg twice a day for 7 days in 6/7 schedule) did not affect the development of tolerance to the pharmacological actions of morphine. 4. It is concluded that activation of x-opiate receptors does not modify the development of tolerance to morphine in the rat.
Journal of Neurochemistry, 2008
Previous evidence demonstrates that low dose morphine systemic administration induces acute thermal hyperalgesia in normal mice through lOR stimulation of the inositol signaling pathway. We investigated the site of action of morphine and the mechanism of action of lOR activation by morphine to NMDA receptor as it relates to acute thermal hyperalgesia. Our experiments show that acute thermal hyperalgesia is blocked in periaqueductal gray with the lOR antagonist CTOP, the NMDA antagonist MK801 and the protein kinase C inhibitor chelerythrine. Therefore, a site of action of systemically administered morphine low dose on acute thermal hyperalgesic response appears to be located at the periaqu-eductal gray. At this supraspinal site, lOR stimulation by systemically morphine low dose administration leads to an increased phosphorylation of specific subunit of NMDA receptor. Our experiments show that the phosphorylation of subunit 1 of NMDA receptor parallels the acute thermal hyperalgesia suggesting a role for this subunit in morphineinduced hyperalgesia. Protein kinase C appears to be the key element that links lOR activation by morphine administration to mice with the recruitment of the NMDA/glutamatergic system involved in the thermal hyperalgesic response.
The Journal of Pain, 2002
Effects of systemic morphine on operant escape responses of rats to thermal stimulation were compared directly with effects on innate licking and guarding responses. For these independent tests, thermal stimulation was delivered via the floor of testing chambers with or without platforms that provided an escape option. The principal findings were (1) administration of 0.5 to 1.5 mg/kg morphine attenuated escape from nociceptive heat and (2) in distinct contrast, licking and guarding responses to heat were enhanced by these doses. When escape responding was calculated as time on the heated plate without licking or guarding, sensitivity to morphine was greater for 44°C than for 47°C or 50°C. Also, escape responses to cold (0°C or 10°C) were unaffected by 1.5 mg/kg morphine. The preferential reduction of heat nociception by morphine was demonstrated also by an operant preference task that gave the animals the option of standing on a cold (10°C) or a hot (45°C) surface. Administration of 0.5 mg/kg morphine increased occupancy of the hot surface. Platform time during operant tests was low and variable for warm stimulation (36°C) and was significantly increased by each level of heat, showing that platform occupancy represented escape from nociception rather than avoidance responses. A lack of significant effects of 1.5 mg/kg morphine on operant performance during cold or warm stimulation controls for effects of systemic morphine other than antinociception.
Ultra-low dose (+)-naloxone restores the thermal threshold of morphine tolerant rats
Journal of the Formosan Medical Association, 2013
Three hours later, morphine (15 mg in 5 ml saline) or saline were given intrathecally. All rats received nociceptive tail-flick test every 30 minutes for 120 minutes after morphine challenge at different temperature (45e52 C, respective). Results: Our results showed that, both co-infusion and post-treatment of ultra-low dose (þ)-naloxone with morphine preserves the antinociceptive effect of morphine. Moreover, in the post administration rats, ultra-low dose (þ)-naloxone further enhances the antinociceptive effect of morphine. Conclusion: This study provides an evidence for ultra-low dose (þ)-naloxone as a therapeutic adjuvant for patients who need long-term opioid administration for pain management.
Effect of periaqueductal morphine injection on thermal response in rats
The Japanese Journal of Physiology, 1986
The effect of morphine injection into the midbrain periaqueductal gray (PAG) was examined on thermal response in rats. Rectal temperature (Tre) was recorded in unanesthetized and unrestrained animals before and after PAG morphine injection of 5 or l0,tg in cold (10°C), neutral (22°C), and hot (34°C) environments. Both doses of morphine cuased hyperthermia. Sixty to 105 min after the injection, Tre rose by 1.0-1.5°C regardless of ambient temperature. Naloxone (2 mg/kg, i.p.) blocked the hyperthermic effects of morphine. Injection sites producing hyperthermia were distributed mostly in the ventral PAG and its ventral environs. The analgesic effect of morphine was examined by the tail-flick test. Locations of morphine injection effective for producing analgesia were restricted to the ventral area of the region responsible for hyperthermia. Magnitude of the hyperthermia did not significantly differ between animals with or without analgesia. The effect of PAG morphine (5 µg) was tested on tail vasomotor response to hypothalamic and scrotal thermal stimulations in urethane anesthetized (1.0 g/kg) animals. Threshold hypothalamic temperature for the vasodilation was lower at a scrotal temperature of 40°C than at 30°C. Following PAG morphine, threshold hypothalamic temperature rose and the difference in threshold hypothalamic temperature at the two scrotal temperatures disappeared. Key words ; morphine, midbrain periaqueductal gray, rectal temperature, vasomotor activity, rat. Morphine has repeatedly been reported to affect body temperature (for references see CLARK and CLARK, 1980). The effect varies with dose and with route of administration. When injected into the midbrain periaqueductal gray (PAG) of rats placed in a thermoneutral environment, both morphine and /3-endorphin elicit dose-dependent increases in rectal temperature (TSENG et al., 1980; WIDDowsoN et
Behavioral Neuroscience, 1998
A flavor paired with morphine shifted to the right the function relating morphine dose to tail-flick latencies and provoked hyperalgesic responses when rats were tested in the absence of morphine. These learned increases in nociceptive sensitivity were not mediated by alterations in tail-skin temperature. Microinjection of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5-phosphonopentanoic acid (AP-5) into the lateral ventricle reversed the hyperalgesic responses but spared the tolerance to morphine analgesia. By contrast, systemic administration of the noncompetitive NMDA receptor antagonist MK-801 or intrathecal infusion of AP-5 reversed the hyperalgesic responses as well as the tolerance to morphine analgesia. The results demonstrate that associatively mediated tolerance to morphine analgesia can co-occur with hyperalgesic responses and are discussed relative to learned activation of endogenous pronociceptive mechanisms. The spinal cord contains mechanisms that inhibit the activity of neurons that receive and transmit nociceptive information (see Willis & Coggeshall, 1991, for a review). These mechanisms can be controlled by interconnected structures in the brainstem, most notably the periaqueductal gray in the midbrain and the nucleus raphe magnus in the medulla, which project to the dorsal horn via the dorsolateral funiculus (see Fields & Basbaum, 1994, for a review). Opioid receptors located at each level play a key role in this descending pain control system, and binding at these receptors mediates the antinociceptive effects of opiate drugs such as morphine (see Yaksh, A1-Rodham, & Jensen, 1988, for a review). The spinal cord also contains pronociceprive mechanisms that facilitate the transmission of nociceptive information and mediate the hyperalgesia that results from tissue or nerve damage as well as from the malaise induced by agents such as LiC1 or the bacterial endotoxin lipopolysaccharide (