SPINAL OPIOIDS AND PAIN CONTROL.
Hartmut Buerkle, M.D. and Tony L. Yaksh, Ph.D.
Departments of Anesthesiology , Muenster, Germany and San Diego, California.
The spinal delivery of opioids for the purpose of altering the pain state is an example of the role played by a specific class of spinal receptors in regulating nociceptive transmission. In models ranging from the frog to the human, the spinal delivery of morphine or other mu opioid agonists at doses which have no effect upon motor function, will produce a potent increase in the nociceptive threshold. We will consider the mechanisms of this action.
Opiate receptors. At present, agents classified as opioids are believed to exert their effect by a specific interaction with one or more subclasses of three opiate receptors designated as: mu, delta and kappa, as defined by bioassay, binding and cloning. Cloning work has shown that these receptors have several common properties: i) 370-400 amino acids; 2-5 glycosylation sites; iii) 7 transmembrane spanning regions; and iv) all are negatively coupled through Gi protein to adenylate cyclase.
Receptor membrane effects. Agonist
occupancy of opioid receptors typically leads to several events which serve to
inhibit the activation of the neuron;
i) µ and ∂ and to some
degree k agonists induce a membrane
hyperpolarization through the activation of an inwardly rectifying K+
channel; ii) inhibition of the opening of voltage sensitive Ca++
channels which will subsequently depress the terminal release of
neurotransmitter from the cell. These
joint actions lead to a powerful, receptor-mediated inhibition that is
typically observed with these opiates.
Spinal opiate action. The local action of opiates (delivered by topical or iontophoretic methods in the spinal cord or systemically in an animal with a spinal transection) will selectively depress the discharge of spinal dorsal horn neurons activated by small (high threshold-slowly conducting C fibers) but not large (low threshold, rapidly conducting Aß afferents).
Intrathecal
administration of opioids will reliably attenuate the response of the animal to
a variety of unconditioned somatic and visceral stimuli which otherwise evoke
an organized escape behavior in all species thus far examined. These effects
occur at doses which have no effect upon motor function. In the case of both the single unit
recording and the in vivo intrathecal work, the antinociception displays similar pharmacologies which demonstrate the
important role of µ and ∂ and to a lesser degree K opioid receptors. Thus, the effects are produced by agents
with selectivity for the µ (morphine and DAMGO) and ∂ (DADL, DPDPE)
receptors and these actions are respectively blocked by selective antagonists
for the µ (CTOP) and ∂ (naltrendole) receptors, as well as
non–selectively by naloxone.
Mechanisms of spinal opiate analgesia. Receptor autoradiography with opiate ligands
or immunohistochemistry have revealed that binding and receptor protein is
limited for the most part to the substantia gelatinosa, the region in which
small afferents show their principal termination. Dorsal rhizotomies result in
a significant reduction in dorsal horn opiate binding, suggesting that a
significant proportion is associated with the primary afferents. This finding is consistent with the presence
of opioid receptor protein being synthesized in and transported from small
dorsal root ganglion cells).
Confirmation
of the presynaptic action is provided by the observation that opiates reduce
the release of primary afferent peptide transmitters such as substance P and
CGRP contained in small afferents.
The presynaptic action corresponds to the ability of opiates to prevent the opening of voltage-sensitive Ca++ channels, thereby preventing release. A post-synaptic action is demonstrated by the ability of opiates to block the excitation of dorsal horn neurons evoked by glutamate, reflecting a direct activation of the dorsal horn. The activation of potassium channels leading to a hyperpolarization was consistent with the direct postsynaptic inhibition.
The joint ability of spinal opiates to reduce the release of excitatory neurotransmitters from C-fibers as well as decrease the excitability of dorsal horn neurons is believed to account for the powerful and selective effect upon spinal nociceptive processing.
This
action mediated by an effect upon receptors at the terminal of the sensory
afferent has an important adjunctive
significance. Input into a given root
(from a specific dermatome) distributes several segments distally after the
afferent has entered the dorsal root entry zone (e.g. an L5 root may have
collaterals that extend as far forward as L1-2). Hence, the rostrocaudal spinal
distribution for the opiate must extend beyond the evident levels of the spinal
segment at which the root enters. This
property may be contrasted to that of a local anesthetic that technically must
act only at the root to block all excitation entering by that root, whereas an
opiate must act theoretically at all terminals. Hence the delivery of small volumes and high concentrations may
be effective only when there is adequate redistribution.
Opiate mechanisms in humans
There is an extensive literature indicating that opiates delivered spinally can induce a powerful analgesia in humans. The pharmacology of this action has been relatively widely studied and it appears certain that m, d and, to a lesser degree, k agonists are effective after intrathecal or epidural delivery. The effects of spinal opiates are reversed by low doses of systemic naloxone. Importantly, the activity of spinally delivered agents in modulating acute nociception in animal models, such as the rodent, the hot plate reveals an ordering of activity that closely resembles that observed in humans for controlling clinical pain states.
Safety.
Few drugs besides local anesthetics or baclofen have been delivered for such extended periods of time with such frequency. It is interesting therefore that only one systematic long term study has been reported in well characterized animal models. It has long been appreciated that high concentrations of morphine may lead to allodynic effects which are not opiate receptor mediated. In recent work with chronic delivery of intrathecal morphine it has been demonstrated that morphine in high concentrations will lead to the formation of aseptic inflammatory masses (granulomas). The origin of these masses in dog models is not clear (e.g. are the opiate receptor mediated?). There are case reports indicating that this phenomena also occurs in humans and may reflect the consequence of high drug concentrations. These data provide continued evidence that continued care is required in the development of new drugs for spinal delivery.
GENERAL REFERENCES
Coffey RJ, Burchiel K. Inflammatory mass lesions associated with intrathecal drug infusion catheters: report and observations on 41 patients. Neurosurgery. 2002 Jan;50(1):78-87.
Wallace M, Yaksh TL. Long-term spinal analgesic delivery: A review of the preclinical and clinical literature. Reg Anesth Pain Med 25: 117-157, 2000
Yaksh TL: Pharmacology and mechanisms of opioid analgesic activity. Act Anaesthesiol Scand 1997; 41: 94-111.
Yaksh, T.L. and Rudy, T.A.: Analgesia mediated by a direct spinal action of narcotics. Science 192:1357-1358, 1976.