naloxone and Hyperesthesia

Our previous study has reported that electroacupuncture (EA) at low frequency of 2 Hz had greater and more prolonged analgesic effects on mechanical allodynia and thermal hyperalgesia than that EA at high frequency of 100 Hz in rats with neuropathic pain. However, how EA at different frequencies produces distinct analgesic effects on neuropathic pain is unclear. Neuronal plastic changes in spinal cord might contribute to the development and maintenance of neuropathic pain. In the present study, we investigated changes of spinal synaptic plasticity in the development of neuropathic pain and its modulation by EA in rats with neuropathic pain. Field potentials of spinal dorsal horn neurons were recorded extracellularly in sham-operated rats and in rats with spinal nerve ligation (SNL). We found for the first time that the threshold for inducing long-term potentiation (LTP) of C-fiber-evoked potentials in dorsal horn was significantly lower in SNL rats than that in sham-operated rats. The threshold for evoking the C-fiber-evoked field potentials was also significantly lower, and the amplitude of the field potentials was higher in SNL rats as compared with those in the control rats. EA at low frequency of 2 Hz applied on acupoints ST 36 and SP 6, which was effective in treatment of neuropathic pain, induced long-term depression (LTD) of the C-fiber-evoked potentials in SNL rats. This effect could be blocked by N-methyl-d-aspartic acid (NMDA) receptor antagonist MK-801 and by opioid receptor antagonist naloxone. In contrast, EA at high frequency of 100 Hz, which was not effective in treatment of neuropathic pain, induced LTP in SNL rats but LTD in sham-operated rats. Unlike the 2 Hz EA-induced LTD in SNL rats, the 100 Hz EA-induced LTD in sham-operated rats was dependent on the endogenous GABAergic and serotonergic inhibitory system. Results from our present study suggest that (1) hyperexcitability in the spinal nociceptive synaptic transmission may occur after nerve injury, which may contribute to the development of neuropathic pain; (2) EA at low or high frequency has a different effect on modulating spinal synaptic plasticities in rats with neuropathic pain. The different modulation on spinal LTD or LTP by low- or high-frequency EA may be a potential mechanism of different analgesic effects of EA on neuropathic pain. LTD of synaptic strength in the spinal dorsal horn in SNL rats may contribute to the long-lasting analgesic effects of EA at 2 Hz.

Topics: Action Potentials; Animals; Bicuculline; Dizocilpine Maleate; Drug Combinations; Electroacupuncture; Excitatory Amino Acid Antagonists; GABA Antagonists; Hyperesthesia; Ligation; Long-Term Synaptic Depression; Male; Methysergide; Naloxone; Narcotic Antagonists; Nerve Fibers, Unmyelinated; Neuralgia; Neuronal Plasticity; Pain Threshold; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Serotonin Antagonists; Spinal Nerves; Synapses; Time Factors

Upon withdrawal from opioids many patients experience a heightened sensitivity to stimuli and an exaggerated pain response. We present evidence that neonatal rats exhibit allodynia and hyperalgesia on acute opiate withdrawal. Postnatal 7 and 21 day rats were used to approximately model a full term human infant and a human child, respectively. The opiate antagonist naloxone was used to precipitate withdrawal at 30 or 120 min after a single acute administration of morphine. Alternatively, rats were allowed to undergo spontaneous withdrawal. Behavioral manifestations of withdrawal syndrome were not observed when naloxone was administered at 30 min post-morphine, but were present when withdrawal was precipitated at 120 min. Spontaneous and precipitated withdrawal from a single acute administration of morphine produced mechanical allodynia and thermal hyperalgesia in postnatal day 7 rats and mechanical allodynia in postnatal day 21 rats. A higher dose of morphine was required to produce mechanical allodynia in postnatal day 21 versus 7 rats but this increase was independent of the analgesic efficacy of morphine at these two ages. The present work illustrates the need to examine the phenomenon of hypersensitivity upon opioid withdrawal in the human pediatric population.

Topics: Age Factors; Animals; Animals, Newborn; Behavior, Animal; Dose-Response Relationship, Drug; Drug Interactions; Hyperalgesia; Hyperesthesia; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Sensory Thresholds; Substance Withdrawal Syndrome; Time Factors

The development of tolerance and dependence to morphine injected onto the spinal cord was examined in a model of chronic pain following spinal cord injury in rats. Intrathecal morphine completely relieved the marked pain-like response of these rats to innocuous mechanical stimuli. The analgesic effect of morphine injected twice daily was, however, diminished within a few days. Tolerance to the antinociceptive effect of morphine assessed with the tail flick test also developed similarly in rats with chronic pain and in normal controls. Both groups exhibited similar signs of naloxone-precipitated withdrawal after 3 weeks of morphine treatment. The results suggest that the presence of chronic pain-like behavior did not prevent the development of morphine tolerance and dependence, even when morphine was used to treat the chronic pain itself.

Topics: Animals; Behavior, Animal; Chronic Disease; Drug Tolerance; Female; Hyperesthesia; Injections, Spinal; Morphine; Naloxone; Narcotic Antagonists; Pain; Rats; Rats, Sprague-Dawley; Reference Values; Spinal Cord Injuries; Substance Withdrawal Syndrome; Substance-Related Disorders

It is known that peripheral nerve injury induces time-dependent changes in dorsal horn function. The current study investigated the time dependency of the effects of intrathecal morphine and MK-801, an N-methyl-D-aspartate antagonist, on the thermal hyperesthesia evoked by unilateral constriction injury to the sciatic nerve in the rat.. In rats with a unilateral constriction injury to the sciatic nerve, paw withdrawal latency against thermal stimulation for the injured paw was typically 3 s less than that for the uninjured paw during the first 5 weeks after the injury. Drugs were administered intrathecally 1 or 5 weeks after the nerve injury.. Intrathecal morphine increased the paw withdrawal latencies of both the injured paw and the uninjured paw in an equally dose dependent manner in the 1-week study. In the 5-week study, morphine increased the paw withdrawal latency of the uninjured paw in a dose-dependent manner, but not that of the injured paw. Intrathecal MK-801 increased the paw withdrawal latency of the injured paw to the level of the uninjured paw in a dose-dependent manner in both the 1- and 5-week studies.. These data indicate that (1) an N-methyl-D-aspartate receptor-mediated spinal facilitation may be the common mechanism maintaining the thermal hyperesthesia evoked by the constriction injury, and (2) the effects of intrathecal morphine on this thermal hyperesthesia are time-dependent.

Topics: Animals; Constriction, Pathologic; Dizocilpine Maleate; Dose-Response Relationship, Drug; Hot Temperature; Hyperesthesia; Injections, Spinal; Male; Morphine; Naloxone; Rats; Rats, Sprague-Dawley; Reflex; Sciatic Nerve; Time Factors

The effects of codeine phosphate and morphine sulfate (2.5, 15.0, and 30 mg/ml/kg; IM) on latency of a jump response elicited by a noxious (61 degrees C) thermal stimulus were studied in White Leghorn cockerels at 15-16 days posthatch. Codeine induced a significant dose-dependent increase in jump response latency (analgesic effect), whereas morphine at each dose induced a significant decrease in jump response latency (hyperalgesic effect). Naloxone (5 mg/ml/kg) reversed the hyperalgesic effect of morphine (30 mg/ml/kg) and potentiated codeine analgesic effects. It is unlikely that codeine analgesic effects in domestic fowl reflect demethylation of codeine to morphine. These opposite codeine and morphine effects may reflect the interaction of these opiates at different populations of opioid receptors or at different substrates.

Topics: Analgesics; Animals; Chickens; Codeine; Dose-Response Relationship, Drug; Hot Temperature; Hyperalgesia; Hyperesthesia; Male; Morphine; Naloxone; Nociceptors

Manipulations of attack parameters in murine agonistic encounters have shown that moderate attack terminating at the first unambiguous display of the upright submissive posture results in nonopioid analgesia. By contrast, attack continuing significantly beyond this behavioural marker results in decreases in nociception mediated by opiodergic mechanisms. However, these effects have only been demonstrated immediately upon termination of encounters. As such, little is known of the influences of agonistic encounters on nociceptive responding beyond this. Tail-flick latencies of male DBA/2 mice that had been exposed to opioid activating attack parameters were established at 15-minute intervals up to 90 min postattack. Data suggest the existence of at least two distinct phases in nociceptive responding with 1) analgesia being evident in the early phase (0-45 min) and 2) short-lasting (detectable only at 75 min postattack) hyperalgesia in the late phase. Further studies revealed both of these effects to be reversed by low (1-10 mg/kg) doses of naloxone. Interestingly, alterations in responsivity to noxious stimulation postmorphine (1-20 mg/kg) administration followed a similar pattern, with analgesia being detectable 0-2 hr and hyperalgesia being evident at 4 hr postinjection of either 10 or 20 mg/kg morphine. However, only the hyperalgesia induced by 20 mg/kg morphine was reversed by 10 but not 1 mg/kg naloxone. These data together suggest a relationship between the dose of morphine required to induce hyperalgesia and the amount of naloxone needed to reverse this response. The naloxone-reversibility of postencounter or morphine-induced hyperalgesia suggests that these effects are not a consequence of the absence of opiates/opioids per se.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aggression; Analgesia; Animals; Dose-Response Relationship, Drug; Hyperalgesia; Hyperesthesia; Male; Mice; Mice, Inbred DBA; Morphine; Naloxone; Pain Measurement; Social Environment; Time Factors

The effects of exceedingly low doses of morphine (3-50 micrograms/kg i.v.) were studied upon the vocalization threshold induced by paw pressure in rats with Freund's adjuvant-induced arthritis. The highest dose used (50 micrograms/kg i.v.) clearly induced an analgesic effect. No significant modification of the vocalization threshold was observed with 30 micrograms/kg. By contrast, a significant hyperalgesic effect resulted with doses of 10 down to 3 micrograms/kg. Maximum hyperalgesia was observed with 6 micrograms/kg.

Topics: Animals; Arthritis, Experimental; Dose-Response Relationship, Drug; Hyperalgesia; Hyperesthesia; Injections, Intravenous; Male; Morphine; Naloxone; Pain; Rats; Rats, Inbred Strains; Sensory Thresholds; Time Factors; Vocalization, Animal

Opioid antagonists selective for delta-, kappa- and mu-receptor subtypes were administered intrathecally in rats prior to determination of response thresholds to noxious heat, pressure and chemical visceral stimulation. All antagonists induced hyperalgesia differentially with two or more stimuli but delta- and mu-blockade failed to alter writhing activity. Thus, the extent of involvement of an opioid receptor subtype in antinociception depends on the type of noxious stimulation.

Topics: Analgesia; Animals; Benzomorphans; Enkephalin, Leucine; Hyperalgesia; Hyperesthesia; Injections, Spinal; Male; Morphinans; Naloxone; Narcotic Antagonists; Pain; Rats; Receptors, Opioid

Behavioural experiments were undertaken to investigate the possible functional significance of opiate receptors located at peripheral endings of primary sensory neurons. The responses of animals to noxious chemical stimuli applied to the ear (ear scratch test) were measured after local pretreatment of these areas with etorphine. Local etorphine administration produced a low dose hyperalgesia and high dose analgesia. Local as opposed to systemic effects of etorphine were inferred from the absence of effects on the contralateral vehicle-treated ear. Systemic administration of naloxone or of a quaternary opiate antagonist (MRZ 2663-BR), which is relatively ineffective in crossing the blood-brain barrier, blocked the low dose hyperalgesic effect of etorphine in the ear scratch test. As a test for the putative hyperalgesic function of peripheral sensory nerve opiate receptors, neonatal rats were treated with capsaicin (50 mg/kg s.c.) to destroy specifically the subpopulation of primary sensory neurons on which the peripheral opiate receptors are thought to be located, without markedly altering pain thresholds. As adults, these neonatally treated rats showed potentiated analgesic responses to systemic morphine, as would be predicted by central 'analgesic' opiate receptors now acting without opposition from peripheral 'hyperalgesic' opiate receptors. These findings suggest that opiate receptors on primary sensory neurons may mediate hyperalgesic functions and that endogenous opioids might normally play a role in the peripheral induction of irritation, inflammation and pain reactions.

Topics: Administration, Topical; Animals; Behavior, Animal; Capsaicin; Etorphine; Hyperalgesia; Hyperesthesia; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Morphine; Naloxone; Neurons, Afferent; Rats; Rats, Inbred Strains; Receptors, Opioid

Topics: Animals; Diprenorphine; Drug Tolerance; Hyperalgesia; Hyperesthesia; Male; Mice; Naloxone

Prostaglandin E2 injected in the rat paw causes hyperalgesia which is antagonized by local injections of opiate and opiate antagonists. In the present investigation in rats it is shown that naloxone has an analgesic effect at doses as low as 2 micrograms/site, injected into the rat hind paw. At a dose that has no analgesic effect (1 microgram/site) naloxone antagonized the analgesia produced by either local or systemic administration of morphine. Local administration of levorphanol (50 micrograms/site) caused a 50% reduction in the intensity of the hyperalgesia induced by prostaglandin E2. A dose four times greater of its isomer, dextrorphan, had little analgesic effect. The present results support the suggestion that this peripheral analgesia is the result of an action of opiates in receptors located at the nociceptors.

Topics: Analgesia; Animals; Dextrorphan; Dinoprostone; Hyperalgesia; Hyperesthesia; Levorphanol; Morphine; Naloxone; Nociceptors; Prostaglandins E; Rats; Receptors, Opioid

Topics: Animals; Hexanones; Hyperalgesia; Hyperesthesia; Ketones; Male; Mice; Naloxone; Pain; Reaction Time; Time Factors

Morphine, enkephalins, nalorphine, naloxone and pentazocine are shown to have a peripheral analgesic effect. In our modification of the Randall-Selitto test these substances were 50--100 times more potent than a standard local anaesthetic, lidocaine. At this peripheral site, naloxone did not antagonize the effect of morphine. Morphine had a marked analgesic effect on the hyperalgesia induced by PGE2 and PGI2, BaCl2, Ca2+ ionophore A23187, isoprenaline but not on that induced by dibutyryl cyclic AMP. It was suggested that the peripheral analgesic effect of morphine is due to an inhibition of adenylate-cyclase activity.

Topics: Analgesics; Animals; Barium; Bucladesine; Endorphins; Enkephalins; Hyperalgesia; Hyperesthesia; Ionophores; Isoproterenol; Lidocaine; Morphine; Nalorphine; Naloxone; Narcotic Antagonists; Nociceptors; Pentazocine; Prostaglandins E; Rats

Pregnant mice were treated with naloxone via subcutaneous implants, from about 5 days prior to parturition. At birth entire litters were cross-fostered so that groups of offspring were exposed to naloxone treated mothers; before birth, after birth to weaning, from about 5 days prior to birth to weaning, or not exposed to naloxone. When tested on a hot-plate at 50 days of age, females either prenatally treated or treated pre- and postnatally showed hyperalgesia to heat. For males, this effect was not evident. This sex difference may have been induced by the cross-fostering procedure.

Topics: Aging; Animals; Body Weight; Female; Hyperalgesia; Hyperesthesia; Male; Mice; Naloxone; Reaction Time; Sex Factors; Time Factors

Morphine injected into the rat cerebral ventricles had a marked analgesic effect, while no effect was observed with pentazocine and naloxone or nalorphine caused a strong hyperalgesia. Administered systemically (IP) naloxone and nalorphine caused a transitory analgesia followed by a long lasting hyperalgesic effect; morphine and pentazocine showed only an analgesic effect. It was concluded that the site of analgesic action of opioid-antagonists is peripheral rather than central. The peptidase-resistant enkephalin-analog, BW 180c, which does not cross the blood brain barrier, caused a marked analgesia by IP administration to paws made hyperalgesic by PGE2 or carrageenin. It is suggested that agents derived from morphine, morphine-antagonists, enkephalins or cGMP devoid of central effect but having a strong peripheral effect may constitute a new class of safer analgesics.

Topics: Analgesics; Animals; Carrageenan; Enkephalins; Hyperalgesia; Hyperesthesia; Injections, Intraperitoneal; Injections, Intraventricular; Morphine; Nalorphine; Naloxone; Narcotic Antagonists; Nociceptors; Pentazocine; Prostaglandins E; Rats

A diurnal rhythm was observed in the responsiveness of mice to nociceptive stimuli and in the hyperalgesic activity of endogenous opioid peptides and may partly account for previous controversy over the direct action of naloxone in opiate-naive animals.

Topics: Animals; Circadian Rhythm; Endorphins; Enkephalins; Hot Temperature; Hyperalgesia; Hyperesthesia; Mice; Naloxone; Reaction Time

Topics: Analgesia; Animals; Body Weight; Female; Humans; Hyperesthesia; Morphine; Morphine Dependence; Naloxone; Rats; Substance Withdrawal Syndrome; Time Factors