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some different perceptions between physiologists and clinicians (who tend to see chronic stimulation as occurring over weeks to months). Once activated this receptor massively amplifies calcium handling and glutamate receptor activation - like a supercharger for a pain stimulus. Thus, it is a great target. Ketamine, Amantadine, dextromethorphan and methadone have NMDA antagonist effects.
Inhibitory receptors are also routinely expressed at
both the pre-synaptic and post-synaptic membranes. Three major examples of these ligand-receptor pairs are opioids (Mu Kappa and Delta receptors), serotonin (5HT), and Norepinepherine (Alpha-2 receptors). When bound to the channel these ligands activate second messenger systems that modify channel kinetics- hyperpolarizing membranes, closing ion channels and interfering with cellular messenging. GABA is an important messenger at the dorsal horn that unfortunately has had mixed results when targeted for pain modulation. For example, benzodiazapines are GABA agonists, but have a variable effect on pain perception ranging from anti-nociceptive to pro-nociceptive in different studies and at different drug concentrations.
Opioid agonists (morphine, meperidine, hydromorphone, oxymorphone, fentanyl) and partial agonists (butorphanol, buprenorphine, nalbuphine) bind to receptors that are repleat through all levels of the pain processing system. Opioid receptors work via channels (as mentioned above) as well as stimulating inhibitory interneurons.
The number of recognized receptor subtypes continues to expand, shedding some light on some important differences in individual responses to different opioids. In general, agonists tend to provide more potent analgesia than partial agonists. It is important to note, however, that opioids may bind to either inhibitory linked g-proteins (decreasing pain signaling) or excitatory linked g-proteins. With chronic administration the excitatory- linked receptors are increasingly manufactured- leading to tolerance and forms of dysphoria or excitement. Several opioids have been shown to directly stimulate glial activation (see section below). So, while opioids
are the cornerstone of acute pain management, they express increasing limitations in the treatment of chronic conditions. Dogs have an extremely effective first pass metabolism of narcotic drugs, and the only oral narcotic that has shown any levels in the plasma of dogs is codeine.
Tramadol has been utilized as an alternative to opioids because of its oral bio-availability in humans. It is an opioid-like drug with about 10-20% of the efficacy of morphine at mu receptors (in people- likely very minimal opioid effects in dogs). It’s effectiveness is improved via additional effects on the noradrenergic and seratonergic systems in humans. In dogs, there is controversy about the efficacy or oral tramadol, although parenteral
tramadol has been shown to be analgesic. Like tramadol, drugs commonly regarded as ‘anti-anxiety’ medications generally target noradrenegic and seratonergic systems in the brain and spinal cord. Amitriptyline and Imipramine are common examples in veterinary medicine.
Specific alpha-two agonist drugs such as dex- medetomidine, romifidine and xylazine also cause a tremendous amount of sedation, making them very useful for acute pain therapy in individuals who would benefit from sedation but less useful in the management of chronic or ongoing pain.
Before leaving the topic of the dorsal horn, a more direct way to maximize drug effects in this location (or to have drug effects in the case of drugs that cannot penetrate the blood-brain barrier) is to administer the drugs by epidural or spinal routes. The most common drugs used in this way are opioids, local anesthetics, alpha-two agonists and ketamine. Epidural catheters may be placed for long-term administration of drugs through this route. Finally, mild electrical stimulus applied to the spinal cord dramatically reduces some forms of neuropathic pain. Spinal cord stimulators are available for this purpose, although application in non-speaking populations poses some difficulty for post-placement assessment.
Brain stem and cortex Serotonin, norepinepherine
and endorphins/opioids are the most well-understood modulators of pain processing in the brain. In addition, psychological state has a profound influence on pain processing. So, in addition to the generally recognized analgesic drugs, anxiolysis becomes a critical feature
in modifying pain messages in the higher centers. Acepromazine is a profound anxiolytic that has a solid place in pain management despite the fact that it is not independently analgesic. However, natural forms of anxiolysis are probably far superior and include touch, companionship, being at home, reduction of stressful inputs, etc. Acupuncture studies using functional MRI have shown reduced activation of brain areas commonly associated with stress.
Glia Glia are constitutively active support cells that can be upregulated to perform immune functions in the central nervous system. They are activated by transmitter over-flow from the synaptic cleft as well as specific compounds (fractaline) released by active neurons. Astrocytes communicate among one another of great distances by non-synaptic gap-junctions and in turn activate microglia through the release of glutamate, cytokines and other proteins. Opioids can directly stimulate glial activation as well. In addition to some less common therapies (such as pentoxyphylline), Centrally acting NSAIDs slow glial activation. Glial activation secondary to opioid use can be slowed or prevented by co-treatment with NMDA antagonists, gabapentin, or low- dose opioid antagonists. Much information has yet to be gained as the glial component has only been reported in
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