Inhibition by spinal morphine of the tail-flick response is attenuated in rats with nerve ligation injury

Ossipov, Michael H.; Lopez, Y.; Nichols, Michael L.; Bian, Di; Porreca, Frank

doi:10.1016/0304-3940(95)12026-z

Cited by 119 publications

(65 citation statements)

References 21 publications

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“…Interactions between opioid exposure and sensitization of primary afferent nociceptive neurons (i.e., by tissue injury or inflammation) have been previously reported [for review see 54,55]. Generally, the development of hyperalgesia resulting from injury undermines the antinociceptive effectiveness of opioids [56,57,58]. The current study suggests that the administration of opiates may also promote the development of allodynia in the injured system.…”

Section: Discussionsupporting

confidence: 52%

The impact of morphine after a spinal cord injury

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Liu

Washburn

et al. 2007

Behavioural Brain Research

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Nociceptive stimulation, at an intensity that elicits pain-related behavior, attenuates recovery of locomotor and bladder functions, and increases tissue loss after a contusion injury. These data imply that nociceptive input (e.g., from tissue damage) can enhance the loss of function after injury, and that potential clinical treatments, such pretreatment with an analgesic, may protect the damaged system from further secondary injury. The current study examined this hypothesis and showed that a potential treatment (morphine) did not have a protective effect. In fact, morphine appeared to exacerbate the effects of nociceptive stimulation. Experiment 1 showed that after spinal cord injury 20 mg/kg of systemic morphine was necessary to induce strong antinociception and block behavioral reactivity to shock treatment, a dose that was much higher than that needed for sham controls. In Experiment 2, contused rats were given one of three doses of morphine (Vehicle, 10, 20 mg/kg) prior to exposure to uncontrollable electrical stimulation or restraint alone. Despite decreasing nociceptive reactivity, morphine did not attenuate the long-term consequences of shock. Rats treated with morphine and shock had higher mortality rates, and displayed allodynic responses to innocuous sensory stimuli three weeks later. Independent of shock, morphine per se undermined recovery of sensory function. Rats treated with morphine alone also had significantly larger lesions than those treated with saline. These results suggest that nociceptive stimulation affects recovery despite a blockade of pain-elicited behavior. The results are clinically important because they suggest that opiate treatment may adversely affect the recovery of function after injury.

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Section: Discussionsupporting

confidence: 52%

The impact of morphine after a spinal cord injury

Hook

Liu

Washburn

et al. 2007

Behavioural Brain Research

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“…We have confirmed the observation that intrathecal morphine is ineffective in increasing mechanical response thresholds, latencies to radiant heat or sensitivity to cold water in rats exhibiting nerve injury-induced allodynia and hyperalgesia (18)(19)(20)(21)(22). Nevertheless, delayed intrathecal NGF infusion was beneficial in restoring morphine-induced antihyperalgesic and antiallodynic effects indicative of neuropathic pain (unpublished data).…”

Section: Ngf Reverses Cck-inducedsupporting

confidence: 79%

“…Several animal studies have confirmed clinical observations that opioids have little or no therapeutic benefit in alleviating neuropathic pain. Thus, in rats that exhibit nerve injuryinduced allodynia and hyperalgesia, intrathecal morphine was found to be ineffective at increasing mechanical response thresholds, or withdrawal latencies to radiant heat or cold water (18)(19)(20)(21)(22). Various hypotheses have been formulated to explain the lack of opioid effectiveness, including a reduction in the number of opioid receptors, and activation of N-methyl-D-aspartate (NMDA) and/or cholecystokinin (CCK) receptors.…”

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confidence: 99%

Spinal NGF Restores Opioid Sensitivity in Neuropathic Rats: Possible Role of NGF as a Regulator of CCK‐Induced Anti‐Opioid Effects

Cahill

Coderre

2000

Pain Research and Management

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The breadth of peripheral effects produced by nerve growth factor (NGF) in nociceptive processing has been well documented. However, less is known about the functional significance of central NGF in nociceptive transmission. The effect of NGF on the nervous system is dependent on the developmental stage. During the prenatal developmental period, NGF is critical for survival of nociceptors; in the postnatal period it regulates the expression of nociceptor phenotype, and in the adult it contributes to pain following an inflammatory insult. The implications for central NGF in the expression and regulation of spinal neuropeptides that are involved in pain mechanisms are reviewed. Knowledge has been gained by studies using peripheral nerve injury models that cause a deprivation of central NGF. These models also give rise to the development of pain syndromes, which encompass spontaneous pain, hyperalgesia and allodynia, routinely referred to as neuropathic pain. These models provide an approach for examining the contribution of central NGF to nociceptive transmission. Chronic pain emanating from a nerve injury is typically refractory to traditional analgesics such as opioids. Recent evidence suggests that supplementation of spinal NGF restores morphine-induced antinociception in an animal model of neuropathic pain. This effect appears to be mediated by alterations in spinal levels of cholecystokinin. The authors hypothesize that NGF is critical in maintaining neurochemical homeostasis in the spinal cord of nociceptive neurons, and that supplementation may be beneficial in restoring and/or maintaining opioid analgesia in chronic pain conditions resulting from traumatic nerve injury.Key Words: Allodynia; Cholecystokinin; Nerve growth factor; Opiate; Pain Le NGF spinal rétablit la sensibilité aux opioïdes chez les rats neuropathiques : rôle possible du NGF comme régulateur des effets anti-opioïdes induits par la cholécystokinine RÉSUMÉ : L'étendue des effets périphériques produits par le facteur de croissance nerveuse (NGF) dans le processus nociceptif est bien documentée. Cependant, la signification fonctionnelle du NGF central dans la transmission nociceptive est moins connue. L'effet du NGF sur le système nerveux dépend du stade de développement de ce système. Pendant la période de développement prénatale, le NGF est essentiel à la survie des nocicepteurs ; dans la période postnatale, il régule l'expression du phénotype des nocicepteurs, et chez l'adulte, il contribue à la douleur résultant d'une atteinte inflammatoire. Les

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“…This result was surprising in itself since CFA-induced inflammation affects lumbar somatosensory inputs while the tail-flick test measures a sacral reflex. However, primary afferent nociceptors have been shown to project both rostrally and caudally in the cervical spinal cord (Abbadie et al, 2002) and L5-L6 nerve injury was found to induce extrasegmental changes extending downward into S1-S2 (Ossipov et al, 1995;Malan et al, 2000;Wang et al, 2003). Furthermore, electrical stimulation of various acupuncture points in the limbs was reported to elicit an inhibition of the tail nociceptive withdrawal reflexes (Romita and Henry, 1996), further supporting the existence of neuronal connections between lumbar and sacral segments.…”

Section: Discussionmentioning

confidence: 91%

Morphine priming in rats with chronic inflammation reveals a dichotomy between antihyperalgesic and antinociceptive properties of deltorphin

et al. 2007

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Abstract-We previously showed that prolonged morphine treatment and chronic inflammation both enhanced delta opioid receptor (␦OR) cell surface density in lumbar spinal cord neurons. Here, we sought to determine whether administration of morphine to rats with chronic inflammation would further increase the bio-availability of ␦OR, and thereby the analgesic properties of the ␦OR agonist deltorphin, over that produced by inflammation alone. We found that chronic inflammation produced by injection of complete Agonists acting through the mu opioid receptor ( OR), such as morphine and its derivatives, induce potent analgesic effects (Bodnar and Klein, 2004). However, they also give rise to undesirable side-effects such as nausea, constipation, and respiratory depression (Colpaert, 1996;Kreek, 1996). In addition, chronic stimulation of OR induces tolerance and physical dependence (Cowan et al., 1988). By contrast, drugs acting on ␦OR produce more limited analgesia, but also give rise to considerably less undesirable side-effects and induce virtually no tolerance (Porreca et al., 1984;May et al., 1989; Sheldon et al., 1990;Szeto et al., 1999;Gallantine and Meert, 2005). For these reasons, ␦OR agonists have been proposed as possible alternatives to OR agonists for the treatment of chronic pain, including neuropathic (Mika et al., 2001;Petrillo et al., 2003;Morinville et al., 2004a) and chronic inflammatory pain (Desmeules et al., 1993;Stewart and Hammond, 1994;Fraser et al., 2000;Hurley and Hammond, 2000;Qiu et al., 2000;Cahill et al., 2003;Petrillo et al., 2003).One of the reasons for the relatively poor analgesic efficiency of ␦OR agonists may be that only a small proportion of ␦OR is actually present on neuronal plasma membranes under baseline conditions (Cheng et al., 1995(Cheng et al., , 1997Elde et al., 1995;Zhang et al., 1998;Cahill et al., 2001a). However, under conditions of chronic inflammation, such as produced in rodents by injection of complete Freund's adjuvant (CFA) in the hind paw, we observed a massive recruitment of ␦OR from intracellular stores to the plasma membrane in neurons of the dorsal horn of the spinal cord Morinville et al., 2004b). This increase in the pharmacological availability of ␦OR was postulated to account for the enhanced antihyperalgesic efficacy of the centrally administered ␦OR agonists reported in conditions of chronic inflammation (Hylden et al., 1991;Stewart and Hammond, 1994;Fraser et al., 1 Present address: Department of Physiology and Biophysics, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada, J1H 5N4. *Corresponding author. Tel: ϩ1-514-398-1913; fax: ϩ1-514-398-5871. E-mail address: alain.beaudet@mcgill.ca (A. Beaudet). Abbreviations: CFA, complete Freund's adjuvant; DRG, dorsal root ganglion; Fluo-DLT, -Bodipy 576/589 deltorphin-I 5-aminopentylamide; i.t., intrathecal/intrathecally; MPAHE, maximum possible antihyperalgesic effect; MPE, maximum possible antinociceptive effect; MS, morphine sulfate; OR, mu opioid receptor; PB, phosphate buffer; RI...

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Inhibition by spinal morphine of the tail-flick response is attenuated in rats with nerve ligation injury

Cited by 119 publications

References 21 publications

The impact of morphine after a spinal cord injury

The impact of morphine after a spinal cord injury

Spinal NGF Restores Opioid Sensitivity in Neuropathic Rats: Possible Role of NGF as a Regulator of CCK‐Induced Anti‐Opioid Effects

Morphine priming in rats with chronic inflammation reveals a dichotomy between antihyperalgesic and antinociceptive properties of deltorphin

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