Hyperalgesic State Research Articles

Peripheral opioid actions and analgesia

W ' ith regard to the question of a peripheral action of opiates in altering nociceptive transmission, the focus article by Hargreaves and Joris makes a cogent argument that where a peripheral injury or irritation results in a reduced threshold, opiate drugs delivered at or near the peripheral terminal can diminish the hyperalgesic state. Support for the case is based on several observations: (1)the total response curve for reducing hyperalgesia after local injection lies to the left of the dose response curve for systemic delivery; (2) agents not thought to cross the blood brain barrier, such as the quaternary forms of certain opioids or those that are polar, have measurable activity in inflammatory pain models. (It must be shown that the agents do not cross the blood brain barrier in quantities sufficient to account for the effect. Quaternary drugs can be demethylated, as with methylatropine, and exert a central action, while even polar compounds, such as morphine or beta-endorphin, can exert central effects after systemic delivery. How much is enough?); and (3) normalization of the hyperalgesic state is limited to the body surface into which the opiate was directly delivered, showing that the change in sensitivity was limited to the site of injection and not to a contralateral site of inflammation. The important question that follows is that of whether the observed effect is mediated by an interaction with an opioid receptor. This can only be established by virtue of the pharmacology of the observed effects as it pertains to the stereospecificity, relative potency, and the antagonists' selectivity known to define opioid receptor activity. The failure

Effects of intrathecal capsaicin and an NK-1 antagonist, CP,96-345, on the thermal hyperalgesia observed following unilateral constriction of the sciatic nerve in the rat

We evaluated the effect of intrathecal (i.t.) capsaicin (CAP) and the NK-1 selective non-peptidic antagonist, CP,96-345, on the thermal hyperalgesia ordinarily observed after unilateral partial ligation of the sciatic nerve in rats. CAP was injected i.t. 2 days after constriction injury. Seven days after partial ligation, the levels of substance P (sP), calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) were the same in the left and right dorsal horns of the lesioned rats which were injected with vehicle (VEH). CAP (75 μg/15 μl of 20% 2-hydroxypropyl-β-cyclodextrin) resulted in an equal reduction (40–50%) in the dorsal horn levels of sP and CGRP, but not VIP. After 7 days i.t. CAP increased the paw withdrawal latency (PWL) of the non-injured hind paw. In contrast, there was no change in the PWL of the injured paw when compared to that of VEH-treated animals. Thus, CAP did not abolish the hyperalgesic state. We concluded that the thermal hyperalgesia after sciatic nerve constriction injury is not mediated by CAP-sensitive C fibers. CP,96-345 given i.t. at a dose which is physiologically active (400 μg) had little effect on the thermal response latency of either the normal or hyperesthetic paw. This provides further evidence that neither the normal pain response nor hyperalgesic state is dependent upon a dorsal horn action of sP.

Incomplete reversibility of an experimentally induced hypocholinergic state: Biochemical and physiological, but not behavioral, recovery

In previous reports, we described the experimental development of a hypocholinergic state in rats following the total replacement of dietary choline by an artificial isostere, N-aminodeanol (NADe). NADe shares most of the physicochemical characteristics of choline (Ch) but is utilized less efficiently in pathways leading to the formation of both acetylcholine and phospholipids. This experimental model mimics many of the features of human degenerative dementias. We now discuss the behavioral and physiological effects of restoring a normal diet after the hypocholinergic state has become well established. The procedure by which that state was induced has been described in detail in earlier publications. After replacing Ch in the diets of weanling rats for 270 days, NADe replaced 70–85% of the phospholipid-bound Ch in plasma, brain and peripheral tissue. When dietary NADe was removed and Ch was restored in the diet, NADe disappeared and erythrocyte (RBC) choline levels returned to normal within 30–60 days. Quinuclidinyl benzilate (QNB) binding showed that muscarinic receptors continued to be depressed in animals remaining on the NADe diet, but returned to control levels in the reversal group. There were no differences in cholinesterase activity among the three treatments. Choline acetyltransferase activity returned to control levels, while continuing to be lower in the NADe animals. Liver lipids were elevated in the latter and not significantly different in the control and reversal groups. Among physiological functions, body weight increased more rapidly in the reversal group than in animals continuing on the NADe diet. Brain weights of the reversal animals were significantly greater than those of animals not reversed, but less than controls. Core body temperatures did not differ from controls at any time during the reversal period. Behaviorally, nociceptive threshlds indicative of sensory-reflexive and sensory-perceptual responses remained significantly below normal, that is, a hyperalgesic state. Reversal animals also remained hyperactive and displayed memory significantly poorer than those on the normal diet, that is, no improvement over animals continuing on NADe. In general, the results suggest that behavioral losses induced by NADe reflect persisting changes in the CNS, despite essentially complete recovery of biochemical parameters. The changes may be morphological or be associated with adaptive changes in other neurochemical events in the CNS.

Release of substance P into the superficial dorsal horn following nociceptive activation of the hindpaw of the rat

Substance P (SP) has been widely proposed as being involved in the transmission of nociceptive information in the dorsal horn of the spinal cord. Formalin injected into the hindpaw as a nociceptive stimulus has been shown to increase the amount of immunoreactive SP in the dorsal horn, perhaps by decreasing SP release from primary afferent neurons. Much is known concerning the release of SP from tissue slices or from the entire spinal cord in vivo. However, less is known about the release patterns of SP in the superficial dorsal horn during the activation of peripheral nociceptors. In this study, noxious pinch applied to and formalin injection into the hindpaw were used as nociceptive stimuli while a stereotaxic push-pull cannula was used to perfuse the L 5 dorsal horn. Experiments were conducted in unanesthetized decerbrate/spinal rats, and radioimmunoassay was used to determine the SP-like immunoreactivity (SPLI) content of collected perfusates. Results demonstrate that graded intensities of noxious mechanical pinch produced progressively increased release of SPLI into the dorsal horn; SPLI release returned to baseline rates following termination of the stimulus. The injection of 100 μl of 5% formalin into the hindpaw produced a biphasic inhibition of SPLI release 0–40 min and60min after formalin injection. The application of a noxious pinch following formalin injection produced an increase in SPLI release which did not return to baseline rates; this may be indicative of production of a hyperalgesic state caused by formalin injection. The results of this study support the concept that formalin injected into the hindpaw activates segmental antinociceptive systems which block SP release and limit nociceptive transmission. These results support evidence that SP may play a limited role in the response to formalin.

Rheumatoid arthritis: determination of pain characteristics and comparison of RAI and VAS in its measurement

The purposes of this study were to determine pain characteristics in female patients with rheumatoid arthritis (RA) and to determine the relationship between the outcome of the Ritchie Articular Index (RAI) and pain intensity as measured by the visual analogue scale (VAS). The sample consisted of 30 female patients with a definite diagnosis of RA and a functional capacity of class II. The results indicated that the pain fluctuated during the day. The intensity level of present pain was lower than that of usual pain. Eight patients reported that their worse pain occurred several times/day. Ache was the word most frequently chosen by the subjects to denote their pain sensations. A high correlation r = 0.86 ( P < 0.01) was found between the scores of RAI and present pain on the VAS. This finding suggests that the pain in RA is associated with the hyperalgesic state induced by the inflammatory condition associated with RA. There was no significant correlation between blood tests like ERS, WBC and VAS or RAI.

Antinociceptive effect of intrathecally administered antiserum against calcitonin gene-related peptide on thermal and mechanical noxious stimuli in experimental hyperalgesic rats

We compared the effects of intrathecal administration of antiserum against calcitonin gene-related peptide (CGRP) between thermo- and mechano-nociceptive responses, using experimental hyperalgesic rats. An intrathecal administration of anti-CGRP antiserum, but not antiserum absorbed by synthetic CGRP, normalized either adjuvant- or carrageenin-induced hyperalgesia both in the paw radiant heat and the paw pressure tests, with little effect on non-hyperalgesic paws. These results suggest that endogenous CGRP, probably present in primary afferents, promotes both thermo- and mechano-nociceptive transmission in the spinal dorsal horn, at least in the hyperalgesic states with inflammations.

Noradrenaline hyperalgesia is mediated through interaction with sympathetic postganglionic neurone terminals rather than activation of primary afferent nociceptors.

In hyperalgesic states, observed commonly as a major symptom of tissue inflammation or after central or peripheral nerve injury, non-noxious stimuli produce pain and noxious stimuli are perceived as more painful than usual. The mechanisms underlying the generation of hyperalgesia are not known. In patients with causalgia (burning pain and severe hyperalgesia after a nerve injury) activation of sympathetic post-ganglionic neurones or application of noradrenaline to painful skin exacerbates pain and hyperalgesia while sympathectomy may afford complete relief. One suggestion is that noradrenaline released from sympathetic post-ganglionic neurons increases the discharge of damaged small-diameter afferents by a direct action on the primary afferents. Here we present a new model for noradrenaline-sensitive hyperalgesia and demonstrate that the site of action of noradrenaline is not on the primary afferents but rather is presynaptic on the sympathetic post-ganglionic terminals.

Effects of ethylenediamine on morphine analgesia and tolerance-dependence in mice

1. 1.|Ethylenediamine, a GABA receptor agonist induced a small hyperalgesic state in mice, but increased morphine analgesia. The interaction with this morphine effect was not dose-dependent. 2. 2.|Ethylenediamine significantly antagonized tolerance development at relatively low doses (5–10 mg/kg). 3. 3.|The GABA mimetic agent increased the frequency of abstinence signs in the naloxone-precipitated morphine withdrawal in mice. 4. 4.|The effect of ethylenediamine on morphine withdrawal was suppressed by the irreversible GABA transaminase inhibitor, γ-vinyl GABA.

The effects of small doses of barbiturate on the activity of primate nociceptive tract cells

The activity of neurons identified as or similar to spinothalamic tract cells was compared in anesthetized, intact monkeys and in unanesthetized, decerebrate or spinalized animals. Background activity and responses to A- and C-fiber volleys were smaller in decerebrate than in the other preparations, suggesting the presence of a tonic descending inhibition of nociceptive tract cells in the decerebrate state. Injections of small doses of sodium pentobarbital caused a slight increase in sensitivity of peripheral receptive fields to mechanical stimuli in some cells, and an increase in responses to squeezing the skin with forceps and to C-fiber volleys. Larger doses of pentobarbital reduced the responses to A- and C-fiber volleys. These observations suggest that the activity of nociceptive tract cells is well preserved in the presence of the doses of pentobarbital we routinely use and are consistent with the hyperalgesic state reported to be produced by small doses of barbiturate.

Decrease of tolerance development to morphine by 5-hydroxytryptophan and some related drugs

The administration of 5-hydroxytrytophan (5-HTP) produced a hyperalgesic state in mice tolerant to the analgesic action of morphine. This effect was counteracted by p-chlorophenylalanine (p-CPA) which uncovered the analgesic effect of the serotonin precursor, observed in nontolerant animals. 5-HTP administered prior to various doses of morphine decreased tolerance to the opiate. This effect was also observed in animals treated with p-CPA, methysergide or reserpine. The administration of Dopa prior to morphine failed to inhibit development of tolerance to the analgesic. These results provide evidence in favour of the hypothesis that tolerance to morphine is related to a change in serotonin metabolism or reactivity (see Discussion) induced by the analgesic.