Opioid analgesics such as morphine are universally regarded as the
most powerful pain-relieving drugs. Morphine acts through the
m-opioid receptor to inhibit signals that transmit pain.

Pain thatfollows direct injury to a peripheral nerve is called neuropathic pain.

Unfortunately, it is still not known what mechanisms underlie this
prevalent pain syndrome. Neuropathic pain is an anomaly because
it is insensitive to morphine as well as other opioid drugs and is
currently best managedwith antidepressants and antiepileptics.

Neuropathic pain may be insensitive to morphine because damage
of primary afferent nerves results in decreased expression of
m-opioid receptors on nociceptors and spinal neurons in the pain
pathway, thus reducing the efficacy of morphine.

In addition, other substances may modulate the efficacy of morphine. For example, when the neuropeptide cholecystokinin (CCK) is applied
to the spinal cord, it reduces the inhibitory effects of morphine.

At the cellular level, m-receptors and CCK receptors are expressed
in the same spinal neurons, suggesting thatCCKmay directly inhibit
actions of morphine by means of signaling mechanisms within a given neuron . Furthermore, activation ofm-receptors increases
release of CCK neuropeptide, which then reduces the effectiveness
of morphine in a feedback manner .

 Thus, multiple mechanisms, including decreased m-receptors and increased CCKinduced
inhibition of morphine, make opioids ineffective in treating
neuropathic pain.