The spinal analgesic role of alpha 2-adrenoceptor subtypes in rats after peripheral nerve section.

Two putative agonists of subtypes of alpha 2-adrenoceptors, guanfacine (alpha 2A) and ST-91 ([2,6-dicthylphenylamino]-2-imidazoline, alpha 2C), were applied intrathecally and their effects on autotomy behaviour and on the flexor reflex before and after sciatic nerve section were examined. Neither drug influenced autotomy during a 17-day observation period. Both drugs dose dependently depressed the flexor reflex in rats with intact sciatic nerves. After axotomy, the sensitivity of the flexor reflex to guanfacine and ST-91 was moderately increased compared to normals. ST-91 i.t. at high doses evoked motor discharges, an effect which was reversed by the alpha 1-adrenoceptor antagonist, WB4101 (2-[2,6-dimethyoxyphenoxyethyl]-aminomethyl-1,4-benzodioxane). Thus, the effect of i.t. clonidine on the flexor reflex and autotomy behaviour observed previously may not involve its action on alpha 2A- and alpha 2C-adrenoceptors. Furthermore, due to its motor effect which may involve activation of alpha 1-adrenoceptors, ST-91 may not be a suitable tool to study the physiological function of spinal alpha 2C-adrenoceptors.

The differential effects of morphine and the alpha 2-adrenoceptor agonists clonidine and dexmedetomidine on the prevention and treatment of experimental neuropathic pain.

The effect of intrathecal morphine (MO) and the alpha 2-adrenoceptor agonists clonidine (CLON) and dexmedetomidine on self-mutilation (autotomy), a behavior that may indicate the presence of neuropathic pain, has been examined in rats. In one experiment, a single dose of MO (50 micrograms), but not CLON (50 micrograms) or saline (SAL), injected 60 min before unilateral sciatic nerve section caused a significant decrease in autotomy during the 28-day observation period. In a second experiment, the same dose of MO administered 15 min after nerve section had no beneficial effect on autotomy compared to CLON or SAL. In a third experiment, MO (10 micrograms), CLON (10 micrograms), and dexmedetomidine (1 microgram), an alpha 2-agonist with higher affinity for the alpha 2-receptor than CLON, or SAL were injected intrathecally twice daily for 21 days starting 24 h after axotomy. The rats administered CLON or dexmedetomidine autotomized significantly less than those receiving MO or SAL at 14 days and 21 days after nerve section. Thus, MO, but not alpha 2-agonists, is beneficial in preventing autotomy, a possible sign of neuropathic pain after nerve injury, whereas alpha 2-agonists, but not opioids, are useful in treating such pain chronically.

Up-regulation of cholecystokinin in primary sensory neurons is associated with morphine insensitivity in experimental neuropathic pain in the rat.

We examined the distribution of mRNA for the peptide cholecystokinin (CCK) with in situ hybridization in adult rat lumbar dorsal root ganglia following unilateral section of the sciatic nerve, as well as the effect of systemic CI 988, a selective antagonist of the CCK type B receptor, applied alone or in combination with intrathecal (i.t.) morphine, on the self-mutilating behavior of rats (autotomy) after axotomy, a sign of neuropathic pain and/or dysesthesia. There was a dramatic increase in the number of neurons in dorsal root ganglia synthesizing the peptide cholecystokinin (CCK) after sciatic nerve section. Furthermore, the autotomy behavior of rats was significantly inhibited by chronic i.t. administration of morphine in conjunction with subcutaneous (s.c.) injection of CI 988. Neither i.t. morphine nor s.c. CI 988 alone produced a comparable effect on autotomy. Our results suggested that up-regulation of the mRNA for CCK in primary afferents after nerve injury may be related to the clinical phenomenon of opioid insensitivity. Thus, coadministration of CCK antagonists in combination with opioids may offer a new approach in treating neuropathic pain.

Intrathecal administration of clonidine suppresses autotomy, a behavioral sign of chronic pain in rats after sciatic nerve section.

The effect of chronic intrathecal (i.t.) administration of the alpha 2 adrenoceptor agonist clonidine on self-mutilation behavior (autotomy) after unilateral transection of the sciatic nerve was studied in rats. Rats injected with 10 micrograms clonidine twice daily for 21 days, starting 1 h before nerve section, autotomized significantly less than saline controls. However, in the few rats which received clonidine and autotomized, clonidine did not delay the onset of autotomy compared to saline controls. Termination of clonidine injection after 21 days resulted in increased autotomy within 1-4 days. No sedation or motor impairment was found after this dose of i.t. clonidine. It is suggested that clonidine may be useful in treating neuropathic pain in humans.