Participation of central descending nociceptive facilitatory systems in secondary hyperalgesia produced by mustard oil

doi:10.1016/0006-8993(96)00631-2

Brain Research

Volume 737, Issues 1–2, 21 October 1996, Pages 83-91

https://doi.org/10.1016/0006-8993(96)00631-2 Get rights and content

Abstract

The present series of experiments were designed to examine a potential role for central descending pain facilitatory systems in mediating secondary hyperalgesia produced by topical application of mustard oil and measuring the nociceptive tail-flick reflex in awake rats. Topical application of mustard oil (100%) to the lateral surface of the hind leg produced a facilitation of the tail-flick reflex that was significantly reduced in spinal transected animals. Mustard oil hyperalgesia was also inhibited in animals that had received electrolytic lesions in the rostral ventromedial medulla (RVM). Intrathecal (i.t.) administration of the non-selective cholecystokinin (CCK) receptor antagonist proglumide (10 μg) prior to mustard oil application completely blocked both the lesser and greater hyperalgesic responses observed in spinal transected and normal animals, respectively, and produced an inhibition of the tail-flick reflex in normal animals. Administration of the selective CCK_B receptor antagonist L-365260 i.t. dose-dependently inhibited mustard oil hyperalgesia (ID₅₀ = 364 ng) at doses approximately 5-fold less than the CCK_A receptor antagonist devazepide (ID₅₀ = 1760 ng). Similar to spinal proglumide, microinjection of the neurotensin antagonist SR48692 (3.5 μg) into the RVM blocked mustard oil hyperalgesia and inhibited the tail-flick reflex. These data suggest that secondary hyperalgesia produced by mustard oil is mediated largely by a central, centrifugal descending pain facilitatory system which involves neurotensin in the RVM and spinal CCK (via CCK_B receptors). The inhibition of the tail-flick reflex produced by mustard oil following spinal or supraspinal administration of receptor antagonists suggests concurrent activation of central descending facilitatory and inhibitory systems.

Introduction

Prolonged noxious stimulation results in enhanced responses to subsequent noxious stimuli (hyperalgesia) [36]. The development of hyperalgesia is believed to be the result of both a sensitization of primary afferent nociceptors and a change in excitability of central nociceptive dorsal horn neurons, termed central sensitization. That hyperalgesia is often observed distant from the site of prolonged noxious stimulation (secondary hyperalgesia) supports a role for the central nervous system (CNS) in the production of this phenomenon 3, 4.

While both peripheral and local spinal mechanisms have been the primary focus of most studies investigating central sensitization, an involvement of central descending pain facilitatory systems has received little attention. The existence of descending systems that enhance spinal nociceptive responses has been well documented. Electrical stimulation, glutamate injection, or neurotensin injection into the rostral ventromedial medulla (RVM) have all been shown to facilitate spinal behavioral and dorsal horn neuron responses to noxious stimulation via descending neuronal projections 28, 29, 30, 39, 40, 41. Additionally, physiologically distinct classes of neurons have been identified within the RVM which are believed to mediate facilitation of spinal nociception [7]. Finally, facilitation of spinal nociception observed in studies involving vagal nerve stimulation 25, 26, 27, illness-induced hyperalgesia [33], and formalin pain [34] all appear to involve pain facilitatory systems which descend from supraspinal sites.

The current series of experiments were designed to further elucidate the role of descending pain facilitatory systems in central sensitization following sustained noxious peripheral input. Mustard oil (allyl isothiocyanate), a chemical irritant which produces a neurogenic inflammation and selectively excites C-fibers 11, 37, was utilized in the current study to produce a secondary hyperalgesia. The tail-flick reflex was used as the nociceptive measure since the reflex remains intact in spinal transected animals and therefore the contribution of supraspinal involvement to hyperalgesia may be assessed. Previous work has identified one specific descending system that facilitates spinal nociception involving neurotensin in the RVM and spinal CCK [31]. Thus, a potential involvement of this system in central sensitization and secondary hyperalgesia produced by mustard oil was investigated.

Section snippets

Animals

Adult male Sprague-Dawley rats (400–450 g.: Harlan, Indianapolis, IN) were used in all experiments. The animals were housed in the AAALAC approved animal care facility in the Bowen Science Building, University of Iowa, where they were singly housed with free access to food and water. The procedures described below were approved by the Institutional Animal Care and Use Committee at the University of Iowa.

Surgical preparation

All animals received at least one of the following four surgical procedures under

Effects of mustard oil in normal and spinal transected animals

Immediately following topical application of mustard oil (20 μl, 100%) to the lateral surface of the left hind leg the animals appeared agitated with frequent biting and vocalizations. This response lasted approximately 5–7 min after which the animals behaved normally for the duration of the experiment. Mustard oil additionally produced a significant facilitation of the tail-flick reflex that was apparent 5 min following application and lasted 60 min (Fig. 1). This effect was maximal

Discussion

The data from the present series of experiments demonstrate that topical application of mustard oil to the lateral surface of the hind leg, approximately 30 mm above the ankle, produces a facilitation of the tail-flick reflex (secondary hyperalgesia). Mustard oil, a chemical irritant which selectively activates C-fibers, was used in the present experiments to provide a prolonged, peripheral nociceptive input 11, 37. Cutaneous application to the lateral surface of the hind leg was chosen based

Acknowledgements

The authors wish to thank Michael Burcham for preparation of the graphics. This work was supported by T32-HL07121 and DA 02879.

References (41)

C.L. Cleland et al.
Pentobarbital prevents the development of C-fiber-induced hyperalgesia in the rat
Pain
(1994)
T.J. Coderre et al.
Contribution of central neuroplasticity to pathological pain:review of clinical and experimental evidence
Pain
(1993)
T.J. Coderre et al.
Increased pain sensitivity following heat injury involves a central mechanism
Behav. Brain Res.
(1985)
G.F. Gebhart
Can endogenous systems produce pain
Am. Physiol. Soc. J.
(1992)
A. Ghorpade et al.
Evidence of a role for N-methyl-d-aspartate (NMDA) receptors in the facilitation of tail withdrawal after spinal transection
Pharmacol. Biochem. Behav.
(1994)
V.J. Lotti et al.
A new potent and selective non-peptide gastrin antagonist and brain cholecystokinin receptor (CCK-B) ligand: L-365260
Eur. J. Pharmacol.
(1989)
S.F. Maier et al.
Endogenous pain facilitory systems - antianalgesia and hyperalgesia
Am. Physiol. Soc. J.
(1992)
P.W. Mantyh et al.
Evidence for cholecystokinin-like immunoreactive neurons in the rat medulla oblongata which project to the spinal cord
Brain Res.
(1984)
P.D. Marley et al.
Cholecystokinin in the rat spinal cord: distribution and lack of effect of neonatal capsaicin treatment and rhizotomy
Brain Res.
(1982)
A.P. Nicholas et al.
Serotonin, substance P and glutamate/aspartate-like immunoreactivities in medullo-spinal pathways of rat and primate
Neuroscience
(1992)

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Research reportParticipation of central descending nociceptive facilitatory systems in secondary hyperalgesia produced by mustard oil

Abstract

Introduction

Section snippets

Animals

Surgical preparation

Effects of mustard oil in normal and spinal transected animals

Discussion

Acknowledgements

Pain

Pain

Behav. Brain Res.

Am. Physiol. Soc. J.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Am. Physiol. Soc. J.

Brain Res.

Brain Res.

Neuroscience

Neuropeptides

Pain

Neurosci. Lett.

Brain Res.

Brain Res.

Brain Res.

Physiol. Behav.

Pain

Brain Res.

The sites of origin of brainstem neurotensin and serotonin projections to the rodent nucleus raphe magnus

J. Neurosci.

Research report
Participation of central descending nociceptive facilitatory systems in secondary hyperalgesia produced by mustard oil