VPT 321: Veterinary Neuropharmacology (2+1) copy 1

MECHANISM OF ACTION

• Opioids act centrally to elevate the pain threshold and to alter the psychological response to pain. They also act peripherally. The pharmacological effects result from interactions with one or more of the four opioid receptors (mu, sigma, kappa and delta). 
• The pharmacological effects vary among the opioid derivatives, depending upon the physiological effects associated with each receptor, its location in the body and the type of interaction between the opioid and the receptor.
• Opiate receptors occur in high density in the dorsal horn of the spinal cord, where they are responsible for modulating pain.
  • μ (Mu) receptors give rise to analgesia and sedation above the spinal cord or in the spinal cord. Interactions with μ receptors also cause euphoria, respiratory depression and physical dependence.
  • κ (Kappa) receptors are responsible for analgesia that is spinal in origin and for miosis and sedation.
  • σ (Sigma) receptors are no longer recognized as a separate class of receptors. Positive interactions between drugs and these receptors provide no analgesia. Rather, many of the adverse effects of the opioids are mediated at these receptors, including dysphoria, hallucinations, respiratory stimulation and some of the vasomotor responses to opioids.
  • δ (Delta) receptors appear to modulate, among other effects, emotional behaviour and immunomodulation. These receptors may also contribute to analgesia.
• All opioid receptors are linked through G-protein to inhibition of adenylate cyclase. They also facilitate opening of potassium channels causing hyperpolarization and inhibit opening of calcium channels. These membrane effects are not linked to decreased cAMP formation.
• Species differences in number of receptors, their location and specificity and selectivity to the various drugs are important to differences in response to the opiates.
• Opioids can interact with these receptors as agonists or antagonists. Pure agonists have high affinity for delta and kappa sites. Some drugs like codeine, methadone and dextropropoxyphene are referred to as weak agonists, since, their maximal effects, both analgesic and unwanted side effects are lower than those of morphine and they do not cause dependence.
• Mixed agonists exhibit variable binding specificities at each receptor sub type, with some sites being agonistic and other sites antagonistic. Partial agonists do the same as mixed agonists, but their positive interaction with the receptors occurs with less than full activity at some of the receptors. Thus many of the varied effects of these drugs result from the agonistic actions at one receptor and antagonistic activity at another.  

Endogenous opioids

• Three families of endogenous opioids have been described. They are β endorphins, enkephalins and dynorphin.
• β endorphins are present in the pituitary gland, hypothalamus, small intestine, placenta and plasma.
• Enkephalins are widely distributed in areas of the CNS that receive afferent nociceptive information. They also exist in the peripheral nervous system, gastrointestinal tract and plasma.
• Dynorphins are believed to function primarily as neuromodulators in the CNS through interaction with the mu, kappa and delta opioid receptors.
• The greatest role of β endorphins is probably modulation of nociception during stress and acupuncture.
• Enkephalins act as inhibitory neurotransmitters and may elicit analgesia through the modulation of substance P release. Enkephalins play a role in acupuncture mediated, analgesia.
• Dynorphins may be most important in nociception at the spinal cord level through activation of kappa receptors.