Spinal analgesia

The actions listed for antagonists are seen with the antagonist alone. All the correlations in this table are based on studies in rats and mice, which occasionally show species differences. Thus, any extensions of these associations to humans are tentative. Clinical studies do indicate that (x receptors elicit analgesia spinally and supraspinally. Preliminary work with a synthetic opioid peptide, [D-Ala, D-Leu ]enkephalin, suggests that intrathecal 8 agonists are analgesic in humans. 

Dynorphin may also influence nociception at the spinal level. The levels of prodynorphin mRNA and immunoreactive dynorphin increase in the chronic inflammatory arthritic model (158). Dynorphin also inhibits morphine or P-endorphin-induced analgesia in naive animals and enhances analgesia in tolerant animals, indicating that this peptide may have a regulatory role in opioid analgesia (159). This effect does not appear to be mediated by a classical opioid receptor, since des-tyrosine dynorphin, which does not bind to opioid receptors, also antagonizes morphine analgesia (160). 

A high concentration of DOPs is found in the olfactory bulb, the neocortex, caudate putamen, and in the spinal cord, but they are also present in the gastrointestinal tract and other peripheral tissues. The functional roles of DOP are less clearly established than for MOP they may have a role in analgesia, gastrointestinal motility, mood and behaviour as well as in cardiovascular regulation [2]. 

The best-understood sites of action of morphine are at spinal and brainstem/ midbrain loci, producing both the wanted and unwanted effects of the opioid. The spinal actions of opioids and their mechanisms of analgesia involve (1) reduced transmitter release from nociceptive C-fibres so that spinal neurons are less excited by incoming painful messages, and (2) postsynaptic inhibitions of neurons conveying information from the spinal cord to the brain. This dual action of opioids can result in a... 

An intriguing area of research on opioids has been the accumulating evidence for plasticity in opioid controls. The degree of effectiveness of morphine analgesia is snbject to modulation by other transmitter systems in the spinal cord and by pathological changes induced by peripheral nerve injury. Thus in neuropathic states, pain after nerve injury, morphine analgesia can be reduced (but can still be effective) and tactics other than dose-escalation to circumvent this will be briefly discussed in Chapter 21. 

Opioids act in the brain and within the dorsal horn of the spinal cord, where their actions are better understood. The actions of opioids important for analgesia and their side-effects involve pre- and postsynaptic effects (1) reduced transmitter release from nerve terminals so that neurons are less excited by excitatory transmitters, and (2) direct inhibitions of neuronal firing so that the information flow from the neuron is reduced but also inhibitions of inhibitory neurons leading to disinhibition. This dual action of opioids can result in a total block of sensory inputs as they arrive in the spinal cord (Fig. 21.5). Thus any new drug would have to equal this dual action in controlling both transmitter release and neuronal firing. 

Figure 21.5 Mechanisms of opioid analgesia at the spinal level. Action potentials in nociceptive afferent fibres invade the terminal and by opening calcium channels (L, N and P-type) cause the release of glutamate and peptides that further transmit pain subsequent to activation of their postsynaptic receptors. Presynaptic opioid receptor activation (mu- and delta-mediated effects have been most clearly shown) opens potassium channels which hyperpolarise the terminal, so reducing transmitter release and inhibiting the postsynaptic neuron...

Complete C-fibre inhibitions can be produced under normal conditions but opiates do not always produce a complete analgesia in some clinical situations, especially when the pain arises from nerve damage. Reasons for this are suspected to be excessive NMDA-mediated activity which is hard to inhibit and the mobilisation of cholecysto-kinin in the spinal cord which can act as a physiological antagonist of opiate actions. The idea that pre-emptive analgesia aids post-operative pain relief by preventing the pain-induced activation of these systems is becoming popular. 

Finally, as outlined above, descending monoamine systems, originating in the midbrain and brainstem that act through the spinal release of noradrenaline and 5-HT, modulate the spinal transmission of pain. Alphai adrenoceptors appear to be important in this role but it is unlikely that behavioural effects such as sedation can be separated from the analgesia. Since both noradrenaline and 5-HT are key transmitters in the control of mood and anxiety and yet also participate in the control of sensory events that lead to... 

QUESTION Have you had the opportunity to look at substance P, possibly in the spinal cord I am thinking about some of the work that Dr. Seiden presented and potentially a role in analgesia. 

Acetaminophen is a centrally acting analgesic that produces analgesia by inhibiting prostaglandin production in the brain and spinal cord. It is an effective and inexpensive analgesic with a favorable risk-benefit profile.9 It should be tried initially at an adequate dose and duration before considering an... 

Intrathecal (IT) Into the subarachnoid space between two of the membranes (meninges) separating the spinal cord from the vertebral column. This route is used for drugs that do not penetrate the blood-brain barrier, but which are required for their central action (e.g., antibiotics). Drugs can also be injected spinally (into the epidural space) for local anaesthesia or analgesia. 

Other options for labor analgesia include spinal analgesia and nerve blocks. 

The nucleus locus coeruleus (LC) in the pons is an important source of noradrenergic projections in the central nervous system, with extensive forebrain, brain stem, and spinal projections (Lindvall and Bjorklund 1974). Particularly relevant to analgesia are projections from the LC to nuclei in the rostral ventromedial medulla (RVM) (see review Moore... 

Another pontine area of interest regarding analgesia is the pedunculopontine tegmental nucleus (PPTN), which is a major brain stem source of cholinergic cells. The PPTN has projections to the RVM and spinal cord (Iwamoto and Marion 1993). The RVM receives input from many brain areas relevant to analgesia, and has projections to the spinal cord (Fields et al. 1991 Zagon 1995). 

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