Opiates cross-tolerance

There are two main treatments for the opiate withdrawal syndrome. One is replacement therapy with methadone or other X agonists that have a longer half-life than heroin or morphine, and produce mild stimulation rather than euphoria. They also produce cross-tolerance to heroin, lessening heroin s effect if patients relapse. Withdrawal is also treated with the 0C2 agonist clonidine, which inhibits LC neurons, thus counteracting autonomic effects of opiate withdrawal — such as nausea, vomiting, cramps, sweating, tachycardia and hypertension — that are due in part to loss of opiate inhibition of LC neurons. 

In 1974, Liebeskind showed the existence of a central pain-suppressive system, and was able to produce analgesia by electrical stimulation of the periventricular gray matter within the brain. This electroanalgesia could be reversed by opiate antagonists, and showed a cross-tolerance with morphine-induced analgesia. These results indicated the existence of a neuronal system that uses an endogenous neuromodulator or neurotransmitter with opiate-like properties. 

Cross-tolerance occurs between all opiates that act primarily via the mu receptors. This is the basis of the methadone substitution therapy which is commonly used to withdraw people who are dependent on heroin or morphine methadone is used because of its relatively long half-life (about 12 hours) and its ease of administration in an oral form. Cross-tolerance does not occur between the opiates and other classes of dependence-producing drugs such as the barbiturates, alcohol or the amphetamines, which act through different mechanisms. 

The prototypes of rigid opiates all have fused ring structures which may contain three (benzomorphans), four (morphinans), five (morphine) or six (oripavines/thebaines) fused rings. All active opiates in these classes, and in the so-called flexible opiates, exhibit cross tolerance and are reversibly blocked by the opiate antagonist naloxone. 

It has been speculated that classical hormonal feedback mechanisms might act to suppress endogenous opioid synthesis when the receptors are occupied by an endogenous opiate-like morphine.61 Enkephalin levels in the brain of morphine-tolerant rats are increased, 1 and there is cross-toler-ance between morphine and Met-enkephalin.62... 

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