Effects of selective and non-selective ℵ-opioid receptor agonists on cutaneous C-fibre-evoked responses of rat dorsal horn neurones

doi:10.1016/0006-8993(87)90265-4

Brain Research

Volume 415, Issue 1, 7 July 1987, Pages 21-29

https://doi.org/10.1016/0006-8993(87)90265-4 Get rights and content

Abstract

We have studied the effects of 3 putative ℵ-opioid receptor agonists, U50488H, ethylketocyclazocine (EKC) and dynorphin A_1–13 (DYN) on the processing of nociceptive information in the dorsal horn of the rat under halothane anaesthesia. Extracellular single unit recordings were made from convergent or multireceptive lumbar dorsal horn neurones, which could be excited by impulses in Aβ and C fibre afferents following transcutaneous electrical stimulation of their ipsilateral hind paw receptive fields and also by noxious and innocuous natural stimuli. Agonists were applied directly onto the surface of the spinal cord. DYN and U50488H consistently produced both a facilitation and inhibition of the C-fibre evoked nociceptive responses of individual cells, these dual effects being relatively insensitive to naloxone antagonism and cancelled each other for the whole population of cells. Aβ fibre-evoked responses were little altered. In contrast, EKC consistently depressed C-fibre transmission in a dose-dependent, naloxone reversible manner, analagous to, but considerably less potent than intrathecal morphine under identical experimental conditions. Agonist-induced effects on neuronal responses to natural stimulation (noxious pinch and innocuous prod) were consistent with the changes observed with the electrically evoked responses. The present results therefore indicate that EKC probably exerts its spinal antinociceptive activity in the rat spinal cord in a manner akin to μ-receptor activation. Results with U50488H and DYN indicate that χ-opioids can excite and inhibit individual neurones but produce no overall change on the whole population, so differing from effects mediated by the other opiate receptors.

Reference (44)

CalthropJ. et al.
The action of kappa agonists on the nociceptive responses of neurones in the medullary dorsal horn of the anaesthetized rat
Life Sci.
(1983)
DickensonA.H. et al.
Electrophysiological studies on the effects of intrathecal morphine on nociceptive neurones in the rat dorsal horn
Pain
(1986)
DickensonA.H. et al.
Opioid receptor subtypes in the rat spinal cord: electrophysiological studies with mu and delta opioid receptor agonists in the control of nociception
Brain Research
(1987)
DickensonA.H.
Topical application of glutamate and substance P onto trigeminal nucleus caudalis produce dorsal horn neuronal inhibitions in the rat
FadenA.I. et al.
Dynorphin induces partially reversible paraplegia in the rat
Eur. J. Pharmacol.
(1983)
GouardèresC. et al.
Opioid binding sites in different levels of rat spinal cord
Neuropeptides
(1984)
GouardèresC. et al.
Autoradiographic localisation of mu, delta and kappa opioid receptor binding sites in rat and guinea pig spinal cord
Neuropeptides
(1985)
GruolD.L. et al.
Dynorphin-A alters the excitability of pyramidal neurones of the rat hippocampus in vitro
Life Sci.
(1983)
HanJ.S. et al.
Dynorphin: potent analgesic effect in the spinal cord of the rat
Life Sci.
(1982)
HeadleyP.M. et al.
Comparison of mu, kappa and sigma preferring agonists for effect on spinal nociceptive and other responses in rats
Neuropeptides
(1984)

HirotaN. et al.

Met-enkephalin and morphine but not dynorphin inhibit noxious stimuli induced release of Substance P from rabbit dorsal horn in situ

Neuropharmacology

(1985)

IwamaT. et al.

Different effects of dynorphin A on in vitro guinea pig hippocampal CA3 pyramidal cells with various degrees of paired-pulse facilitation

Neurosci. Lett.

(1986)

KhachaturianH. et al.

Dynorphin immunocytochemistry in the rat central nervous system

Neuropeptides

(1982)

LahtiR.A. et al.

Properties of a selective kappa agonist, U50488H

Life Sci.

(1982)

McFadzeanI. et al.

Kappa opiate receptor activation in the rat locus coeruleus

Neuropeptides

(1984)

MillanM.J. et al.

Spinal cord dynorphin may control chronic pain via a kappa-opioid receptor in the rat

Brain Research

(1985)

PierceyM.F. et al.

Analgesic activity of intraspinally administered dynorphin and ethylketocyklazocine

Eur. J. Pharmacol.

(1982)

PrzewlockiR. et al.

Mixed opioid/non-opioid effects of dynorphin and dynorphin-related peptides after their intrathecal injection in rats

Neuropeptides

(1983)

PrzewlockiR. et al.

Analgesic effects of mu, delta and kappa-opiate agonists and, in particular, dynorphin at the spinal level

Life Sci.

(1983)

SlaterP. et al.

Autoradiographic localization of opiate kappa receptors in the rat spinal cord

Eur. J. Pharmacol.

(1983)

TungA.S. et al.

In vivo evidence for multiple opiate receptors mediating analgesia in the rat spinal cord

Brain Research

(1982)

VincentS.R. et al.

Dynorphin immunoreactive neurones in the central nervous system of the rat

Neurosci. Lett.

(1982)

Cited by (93)

Pain System
2015, The Rat Nervous System: Fourth Edition
The pain system is the set of neural pathways responsible for mediating the sensations interpreted as pain. Sensory-discriminative aspects of pain originating from the body surface include coding for the precise quality, intensity, duration, and location of the sensory input. Pain arising from visceral organs and other deep structures of the body is usually poorly localized and has a different, dull aching quality. Neurons that signal the sensory-discriminative components of pain sensation encode these aspects of painful stimuli in a manner generally similar to that used by other sensory systems, such as the visual and auditory systems. However, pain more powerfully engages mechanisms of attention and arousal in limbic regions of the brain than is generally the case for vision and audition. The sense of pain is more often accompanied by strong motivational-affective responses, including emotional reactions (suffering, anxiety, depression), somatic and autonomic reflexes, and endocrine changes. This is especially true for visceral pain. The neural pathways that mediate the motivational-affective components of pain overlap to some extent those involved in pain sensation, but also include additional neural structures and pathways. A better understanding of many complex mechanisms and circuitries underlying sensory dysfunction gained through the study of animal models has translated into existing successful therapies. Focus on the neuroplasticity and dysfunctional mechanisms induced in chronic pain models is leading to the development of better future therapeutics.
Early-in-life bladder inflammation alters U50,488H but not morphine-induced inhibition of visceromotor responses to urinary bladder distension
2013, Neuroscience Letters
Citation Excerpt :
U50,488H has been demonstrated to have both facilitatory and inhibitory effects on the spinal dorsal horn. For example, low doses of U50,488H produce either facilitation or inhibition of spinal dorsal horn neuronal responses to electrical C-fiber stimulation, noxious pinch, or formalin, while greater doses consistently produce inhibition of spinal dorsal horn neuron responses to these stimuli [9,20]. If U50,488H acted centrally in the present study, then i.v. administration of the 1 mg/kg dose may have been sufficient to produce a net inhibition of spinal dorsal horn neurons to bladder input in groups AA, AZ, and ZA resulting in the decrease in VMRs to UBD.
Previous research has suggested that early-in-life (EIL) exposure to bladder inflammation impairs the function of endogenous opioid inhibitory system(s) and may contribute to the development of chronic bladder pain. This study examined how acute adult and/or prior EIL exposure to bladder inflammation altered the inhibitory effects of systemic κ- and μ-opioid agonists on the visceromotor reflex (VMR) to urinary bladder distension (UBD). Female rats were exposed intravesically EIL (P14–P16) to either the inflammatory agent zymosan or anesthesia-alone, and then rechallenged as adults (12–17 weeks) with either anesthesia-alone or zymosan. The VMR to 60 mmHg UBD was measured after cumulative intravenous (i.v.) administration of 1 mg/kg and 4 mg/kg of either the κ-opioid agonist U50,488H or the μ-opioid agonist morphine. Morphine produced dose-dependent inhibition of the VMR to UBD in all groups, and U50,488H produced dose-dependent inhibition of the VMR to UBD in all but one group. Animals that received bladder inflammation both EIL and as adults showed significantly augmented VMRs to UBD (>100% baseline values) following 1 mg/kg of U50,488H and diminished inhibition of VMRs following 4 mg/kg of U50,488H when compared with other groups. In contrast, neither EIL nor adult bladder inflammation markedly altered the inhibition of the VMR to UBD produced by either 1 or 4 mg/kg of i.v. morphine. These data suggest EIL and adult exposure to bladder inflammation selectively decreases the inhibitory effects of κ-opioids and thereby may enhance bladder hypersensitivity in patients with painful bladder syndromes.
Opioid Analgesics
2011, Pain Management, Second Edition
Attenuation of cannabinoid-induced inhibition of medullary dorsal horn neurons by a kappa-opioid receptor antagonist
2010, Brain Research
Citation Excerpt :
Previous studies that have examined the effect of KOR agonists on dorsal horn neurons have produced mixed results. Iontophoretic or direct spinal cord application of KOR agonists have caused either excitation or inhibition or had no effect on the activity of dorsal horn nociceptive neurons (Dong et al., 1991; Hylden et al., 1991; Knox and Dickenson, 1987; Sullivan and Dickenson, 1991; Wang et al., 1999). These previous studies are in contrast to the relatively consistent findings of cannabinoid receptor mediated inhibition of spinal and MDH neurons, again raising questions as to the role of endogenous kappa opioids in cannabinoid-induced antinociception.
The kappa-opioid receptor (KOR) antagonist norbinaltorphimine (nor-BNI) attenuates behavioral antinociception produced by spinal administration of the cannabinoid receptor agonist delta-9-tetrahydorcannabinol (THC). The present study examined the ability of nor-BNI to prevent cannabinoid-induced inhibition of medullary dorsal horn (MDH) nociceptive neurons and antinociception produced by the cannabinoid agonist WIN 55,212-2 (WIN-2). Extracellular, single-unit recordings of lamina I and lamina V MDH neurons were performed in urethane anesthetized rats. Heat-evoked activity was measured before and after local brainstem application of nor-BNI or vehicle followed by WIN-2. In both lamina I and lamina V neurons, prior application of nor-BNI prevented the inhibition of heat-evoked activity by WIN-2. In separate experiments, the contribution of KOR to cannabinoid-induced increases in heat-evoked head withdrawal latencies was assessed in lightly urethane-anesthetized rats. Antinociception produced by intrathecal administration of WIN-2 and THC was attenuated by prior administration of nor-BNI. In contrast, antinociception produced by the cannabinoid CP55940 remained unaffected by prior administration of nor-BNI. These results indicate that cannabinoid inhibition of nociceptive reflexes produced by WIN-2 and THC may result from inhibition of dorsal horn neurons through a KOR-dependent mechanism.
Neuro-Reflexotherapy for the Management of Myofascial Temporomandibular Joint Pain: A Double-Blind, Placebo-Controlled, Randomized Clinical Trial
2008, Journal of Oral and Maxillofacial Surgery
To assess the efficacy of neuro-reflexotherapy intervention (NRT) for treating temporomandibular joint dysfunction attributed to myofascial pain. Neuro-reflexotherapy intervention consists of the temporary implantation of epidermal devices in trigger points in the back and ear. It has shown efficacy, effectiveness, and cost-effectiveness in treating subacute and chronic common back pain. No study, however, has explored its efficacy in treating myofascial temporomandibular joint pain (MF/TMJP).
This was a randomized, double-blind, placebo-controlled trial. Patients with MF/TMJP for more than 3 months in spite of conservative treatment, and with no evidence of major structural damage in the joint, were recruited at the Maxillofacial Department of the Hospital Clínico Universitario, a teaching hospital in Madrid, Spain. Patients were randomly assigned to an intervention group and to a control group. Patients in the treated group underwent 2 NRTs, immediately after baseline assessment and 45 days later. Sham interventions in the control group consisted of placement of the same number of epidermal devices within a 5-cm radius of the target zones. In both groups, conservative treatment during follow-up was allowed and recorded. Patients underwent clinical evaluations on 4 occasions: 5 minutes before intervention, 5 minutes after intervention, and 45 and 90 days later. The preintervention assessment was performed by the physician at the hospital service who included the patient in the study. The 3 follow-up assessments were performed independently by 1 of 2 physicians who had no connection with the research team, and who were blinded to patients' assignments. The primary outcome variable was level of pain severity during jaw movements at the last assessment (90 days), and the key comparison of interest was change in pain over time (pain levels at baseline and at 90 days). Level of pain was measured using a visual analog scale (VAS).
Fifty-one patients with MF/TMJP were recruited into the study. Random assignment allocated 27 patients to the intervention group, and 24 to the control group. Differences in pain severity in favor of the intervention group appeared immediately after the intervention, persisted for 45 days, and increased after the second intervention. Differences at last follow-up were highly clinically and statistically significant (4 to 5 points on the VAS, P = .000), allowing for patients in the intervention group to cease drug treatment (P = .005). There were no differences in the evolution of crepitus or clicking in the joint. There were no clinically relevant side effects associated with the intervention.
For patients in whom conservative treatment has failed, NRT improves the chronic pain associated with MF/TMJP syndrome.
Inhibition of tolerance to spinal morphine antinociception by low doses of opioid receptor antagonists
2007, European Journal of Pharmacology
Ultra-low doses of opioid receptor antagonists inhibit development of chronic spinal morphine tolerance. As this phenomenon mechanistically resembles acute tolerance, the present study examined actions of opioid receptor antagonists on acute spinal morphine tolerance. In adult rats, administration of three intrathecal injections of morphine (15 μg) at 90 min intervals produced a significant decline of the antinociceptive effect and loss of agonist potency in both the tail-flick and paw-pressure tests. These reduced responses, indicative of acute tolerance, were blocked by co-injection of morphine (15 μg) with naltrexone (NTX, 0.05 ng), D–Phe–Cys–Tyr–D–Trp–Orn–Thr–Pen–Thr–NH2 (CTAP, 0.001 ng), naltrindole (0.06 ng), or nor-binaltorphimine (0.1 ng). Repeated injections of CTAP, naltrindole, or nor-binaltorphimine without morphine elicited a delayed weak antinociceptive response which was blocked by a high dose of naltrexone (2 μg). In another set of experiments, administration of low dose spinal (0.05 ng) or systemic (0.01 μg/kg) morphine produced a sustained thermal hyperalgesia. This response was blocked by opioid receptor antagonists at doses inhibiting development of acute morphine tolerance. Lastly, an acute spinal injection of morphine (15 μg) with naltrexone (0.05 ng) produced a sustained analgesic response; this was antagonized by adenosine receptor antagonist, 8-phenyltheophylline (3 μg). The results show that ultra-low doses of opioid receptor antagonists block acute tolerance to morphine. This effect may result from blockade of opioid excitatory effects that produce a latent hyperalgesia that then contributes to induction of tolerance. The sustained antinociception produced by combination of morphine with an opioid receptor antagonist shows dependency on the adenosine receptor activity.

View all citing articles on Scopus

: A preliminary account of this work has appeared (ref. 8).

View full text

Effects of selective and non-selective ℵ-opioid receptor agonists on cutaneous C-fibre-evoked responses of rat dorsal horn neurones

Abstract

Life Sci.

Pain

Brain Research

Eur. J. Pharmacol.

Neuropeptides

Neuropeptides

Life Sci.

Life Sci.

Neuropeptides

Neuropharmacology

Neurosci. Lett.

Neuropeptides

Life Sci.

Neuropeptides

Brain Research

Eur. J. Pharmacol.

Neuropeptides

Life Sci.

Eur. J. Pharmacol.

Brain Research

Neurosci. Lett.